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Analgesia en pacientes con ERC Francisco José de la Prada Alvarez Servicio de Nefrología Hospital Son Dureta.

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Presentación del tema: "Analgesia en pacientes con ERC Francisco José de la Prada Alvarez Servicio de Nefrología Hospital Son Dureta."— Transcripción de la presentación:

1 Analgesia en pacientes con ERC Francisco José de la Prada Alvarez Servicio de Nefrología Hospital Son Dureta

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4 4 M01-ANTIINFLAMATORIOS Y ANTIRREUMÁTICOS NO ESTEROIDEOS Ver en el grupo N02B otros analgésicos y antiinflamatorios no esteroideos disponibles en el hospital NOMBRE GENÉRICO PRESENTACIÓNVIANOMBRE COMERCIAL DiclofenacAmp 75 mg/3 ml Comp 50 mg Sup 100 mg IM, IV OR REC Voltaren IbuprofenoJbe 100 mg/5ml Comp 400 mg Comp 600 mg Sobres 200 mg OR Dalsy jarabe Neobrufen IndometacinaCaps 25 mg Sup 100 mg OR REC Inacid, Artrinovo IsonixinaSup inf 200 mgRECNyxin PiroxicamCaps 20 mg Comp 20 mg OR Sasulen, Feldene 20, Vitaxicam, Feldene flas Nota 1: Otros medicamentos del grupo de los AINEs como por ejemplo: Ketoprofeno (Arcental, Fastum, Orudis), Naproxeno (Naprosyn), Aceclofenaco (Airtal, Falcol, Gerbin), Fenbufeno (Cincopal), Flurbiprofeno (Froben), Namebutona (Dolsinal,, Relif), Tenoxicam (Reutenox, Tilcotil), Meloxicam (Movalis) y Tolmetin (Artrocaptin) son medicamentos no incluidos en la Guía y se consideran equivalentes terapéuticos de los AINEs incluidos. Consultar programa de intercambio.

5 5 N02B-Analgésicos no narcóticos y antipiréticos Ver en grupo M01 otros analgésicos no narcóticos y antipiréticos NOMBRE GENÉRICOPRESENTACIÓNComNOMBRE COMERCIAL Acetilsalicilato de lisina (1)(4) Sobres 1,8 g Vial 900 mg/5 ml OR IM,IV Inyesprin oral forte Inyesprin iny(4) Acido AcetilsalicílicoComp 500 mg Comp 300 mg Comp 125 mg OR Ácido Acetilsalicilíco, Adiro, Aspirina Aspirina infantil KetorolacoComp 10 mg Amp 30 mg/1 ml OR IV. IM Droal, Toradol Metamizol (Dipirona) (Noramidopirina) Amp 2000 mg/5 ml Caps 575 mg Sup 1 g Sup 500 mg IV, IM, OR OR REC Nolotil, Lasain ParacetamolComp 500 mg Gts 100 mg/ml (2) Sup 150 mg Sup 250 mg Vial 1g/100ml OR REC IV Termalgin, Dolgesic, Gelocatil (650 mg) Apiretal Febrectal Lactante Melabon Infantil Perfalgan Paracetamol +CodeínaComp 300mg +15mg Comp 650 mg + 30 mg OR Termalgin Codeína; Gelocatil Codeina Nota 1: 1,8 g de Acetilsalicilato de lisina=1g de Acido Acetil Salicílico. Nota 2: gota=4 mg Nota 3: Propacetamol es un precursor del Paracetamol. Propacetamol 1 g libera Paracetamol 500 mg.

6 6 Opioides Los opiodes agonistas son aquellos que al fijarse al receptor mu dan lugar a una respuesta farmacológica, que en este caso es la eliminación del dolor.

7 7 Opioides Los opiodes antagonistas son aquellos que también se unen al receptor mu, pero ello no va seguido de una respuesta farmacológica, es decir, en este caso no se produciría analgesia.

8 8 Opioides Existe otro tipo de opioides denominados agonistas- antagonistas, que son capaces de actuar como agonistas sobre un tipo de receptores y como antagonistas sobre otro tipo, por lo que producen respuestas imprevisibles. En pacientes que reciben agonistas puros, los agonistas-antagonistas pueden precipitar reacciones de abstinencia.

9 9 Semivida corta Semivida larga Para dolor moderado-severo Agonistas puros MorfinaMetanol PetidinaLevorfanol Heroina Fentanilo Sulfentanilo Tramadol Oxicodona Oximorfona Para dolor ligero-moderado CodeinaTramadol DihidrocodeinaOxicodona Dextropropoxifeno

10 10 Semivida corta Semivida larga Agonistas- Antagonistas PentazosinaButorfanol NalbufinaDezocina Meperidina Agonistas parciales Buprenorfina

11 11 Tratamientos de rescate potenciales para el dolor intercurrente o irruptivo en pacientes con cancer Opioides utilizados para el dolor crónico de base: Agonistas puros preferentemente en formas de liberación retardada –Morfina de liberación lenta –Fentanilo via transdermica Tratamiento de rescate: Agonistas puros en forma de liberación rápida o vias de absorción rápida: –Morfina por via parenteral. –Fentanilo por via transmucosa oral.

12 12 Tratamientos de rescate potenciales para el dolor intercurrente o irruptivo en pacientes con cancer Opioides utilizados para el dolor crónico de base: Agonistas parciales: –Buprenorfina de liberación transdermica. Tratamiento de rescate: –Agonistas parciales: buprenorfina sublingual. –Agonistas puros: Morfina por via parenteral. Fentanilo por via transmucosa oral.

13 13 DOSIS EQUIANALGESICAS ENTRE LOS DISTINTOS OPIOIDES ADMINSTRADOS POR VIA ORAL Morfina mg Meperidina 300 mg Metadona mg Tramadol mg Codeina 400 mg Dihidrocodeina 240 mg Hidromorfona 7,5 mg Levorfanol 4 mg Oxicodona 30 mg

14 14 Equivalent opioid doses Drug Time to onset (minutes) Oral dose (mg) Parenteral dose (mg) Morphine sulfate parenteral 10 q4 hr Morphine sulfate oral (MSIR, Roxanol)15 to 6030 q4 hr Morphine sulfate controlled release (MS contin, Oramorph) 90 q12 hrnot available Codeine10 to q4 hr100 to 120 q4 hr Oxycodone (Percocet, Percodan, Tylox)15 to 3015 to 20 q4 hr not available Oxycodone controlled release (Oxycontin) 15 to 3045 to 60 q12 hr not available Hydromorphone (Dilaudid)15 to 308 q4 hr q4 hr Levorphanol (Levodromoran)30 to 904 q6 to q8 hr 2 q6 to q8 hr Meperidine (Demerol)10 to q2 to q3 hr 100 q2 to q3 hr Methadone (Dolophine)30 to 6020* q6 to q12 hr 10 q6 hr * A dose ratio of 1:4 (1 mg of oral methadone = 4 mg of oral morphine) is used for patients receiving less than 90 mg of morphine. Patients receiving 90 to 300 mg/day receive methadone at a ratio of 1:8. Finally, a ratio of 1:12 is used for patients receiving morphine doses greater than 300 mg/day. Equivalent opioid doses

15 15 Buprenorphine: Equianalgesic Dose –Oral: n/a –Parenteral: 0.4 mg – Initial Oral Dose –Children: n/a –Adults: n/a Butorphanol: Equianalgesic Dose –Oral: n/a –Parenteral: 2 mg – Initial Oral Dose –Children: n/a –Adults: n/a Levorphanol: Equianalgesic Dose –Oral: Acute: 4 mg; Chronic: 1 mg –Parenteral: Acute: 2 mg; Chronic: 1 mg – Initial Oral Dose –Children: 0.04 mg/kg –Adults: 2-4 mg/kg Meperidine: Equianalgesic Dose –Oral: 300 mg –Parenteral: 75 mg – Initial Oral Dose –Children: Not recommended –Adults: Not recommended Opioid Analgesics - Initial Oral Dosing Commonly Used for Severe Pain

16 16 Opioid Analgesics - Initial Oral Dosing Commonly Used for Severe Pain Hydromorphone: Equianalgesic Dose –Oral: 7.5 mg –Parenteral: 1.5 mg – Initial Oral Dose –Children: 0.06 mg/kg –Adults: 4-8 mg Methadone: Equianalgesic Dose –Oral: 10 mg –Parenteral: 5 mg – Initial Oral Dose –Children: 0.2 mg/kg –Adults: 5-10 mg Morphine: Equianalgesic Dose –Oral: 30 mg –Parenteral: 10 mg – Initial Oral Dose –Children: 0.3 mg/kg –Adults: mg Nalbuphine: Equianalgesic Dose –Oral: n/a –Parenteral: 10 mg – Initial Oral Dose –Children: n/a –Adults: n/a

17 17 Opioid Analgesics - Initial Oral Dosing Commonly Used for Severe Pain Pentazocine: Equianalgesic Dose –Oral: 50 mg –Parenteral: 30 mg – Initial Oral Dose –Children: n/a –Adults: n/a Oxycodone: Equianalgesic Dose –Oral: 20 mg –Parenteral: n/a – Initial Oral Dose –Children: 0.3 mg/kg –Adults: mg Oxymorphone: Equianalgesic Dose –Oral: 1 mg –Parenteral: n/a – Initial Oral Dose –Children: n/a –Adults: n/a From "Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain,"Am Pain Soc, Fifth Ed.

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19 19 N02A-Analgésicos narcóticos (Opioides) NOMBRE GENÉRICOPRESENTACIÓNVIANOMBRE COMERCIAL BuprenorfinaComp 0,2 mg Amp 0,3 mg/1 ml SL IM, IV Buprex CE CodeínaComp 28 mgORCodeisan Dihidrocodeína (Hidrocodona)Comp 60 mgORContugesic Fentanilo (2)Parche 2,5 mg (3) Parche 5 mg (3) Parche 10 mg (3) TOP Durogesic 25 Durogesic 50 Durogesic 100 MetadonaAmp 10 mg/1 ml Comp 5 mg Comp 40 mg SC, IM OR Metasedin CE Morfina cloruroAmp 10 mg/1 ml (sin conservantes) Vial 400 mg/20 ml (vial multidosis, sin conservantes) Amp 10 ml. SC, IV, IM SC IV, IM Cloruro Mórfico Braun 1 % CE Morfina Braun 2 % s/c CE Morfina Braun 4 % s/c CE Morfina clorhidratoJbe 10 mg/mlORBrompton FM CE Morfina sulfatoComp 10 mg Comp 20 mg OR Sevredol CE (1) Morfina sulfato retardComp 10 mg Comp 30 mg Comp 60 mg Comp 100 mg OR MST Continus CE Petidina (Meperidina)Amp 100 mg/2 mlSC, IM, IVDolantina CE TramadolCaps 50 mg Comp retard 200 mg Comp retard 300 mg Amp 100 mg/2 m OR SC, IM, IV Adolonta, Tralgiol Zytram CE: Control de estupefacientes. Nota 1: Comprimidos ranurados. Nota 2: Uso restringido para tratamiento del dolor crónico. Nota 3: Los parches de 2,5, 5 y 10 mg liberan respectivamente 25, 50 y 100 mcg/h durante 72 h.

20 20 N02B-Analgésicos no narcóticos y antipiréticos Ver en grupo M01 otros analgésicos no narcóticos y antipiréticos NOMBRE GENÉRICOPRESENTACIÓNComNOMBRE COMERCIAL Acetilsalicilato de lisina (1)(4) Sobres 1,8 g Vial 900 mg/5 ml OR IM,IV Inyesprin oral forte Inyesprin iny(4) Acido AcetilsalicílicoComp 500 mg Comp 300 mg Comp 125 mg OR Ácido Acetilsalicilíco, Adiro, Aspirina Aspirina infantil KetorolacoComp 10 mg Amp 30 mg/1 ml OR IV. IM Droal, Toradol Metamizol (Dipirona) (Noramidopirina) Amp 2000 mg/5 ml Caps 575 mg Sup 1 g Sup 500 mg IV, IM, OR OR REC Nolotil, Lasain ParacetamolComp 500 mg Gts 100 mg/ml (2) Sup 150 mg Sup 250 mg Vial 1g/100ml OR REC IV Termalgin, Dolgesic, Gelocatil (650 mg) Apiretal Febrectal Lactante Melabon Infantil Perfalgan Paracetamol +CodeínaComp 300mg +15mg Comp 650 mg + 30 mg OR Termalgin Codeína; Gelocatil Codeina Nota 1: 1,8 g de Acetilsalicilato de lisina=1g de Acido Acetil Salicílico. Nota 2: gota=4 mg Nota 3: Propacetamol es un precursor del Paracetamol. Propacetamol 1 g libera Paracetamol 500 mg.

21 21 Codeina Opioide estructuralmente relacionada con la morfina. Es un alcaloide presente en la Papaver somniferum. Estructuralmente es la metilmorfina y existen estudios que sugieren que sus efectos son, al menos en parte, consecuencia de la desmetilación en el organismo a morfina que sería el principio activo. Sus propiedades analgésicas son similares a las de la morfina pero su potencia es sólo un 12%. La codeína se comporta como un agonista opioide puro de los receptores Mu y, por esta razón, su mecanismo de acción y los efectos derivados de este son, en principio, similares a los de la morfina

22 22Codeina Los opioides que actúan sobre el receptor mu aminoran la transmisión en la médula espinal, mediante una inhibición relacionada con la dosis, de la actividad del tracto neural. En los ganglios basales del cerebro, los opioides activan el sistema inhibidor descendente, que limita la transmisión del dolor a la altura de la médula espinal. Los opioides también producen cambios en el cerebro, lo que provoca una alteración de las respuestas emocionales y aminoran en gran medida la percepción del dolor.

23 23 Properties of opioid receptors Mu Mu1 Supraspinal analgesia Bradycardia Sedation Mu2 Respiratory depression Euphoria Physical dependence Delta Spinal analgesia Respiratory depression Kappa Spinal Analgesia Respiratory depression Sedation Sigma Dysphoria, delirium Hallucinations Tachycardia, hypertension

24 24 Codeina DOSING: ADULTS or ELDERLY Doses >1.5 mg/kg body weight are not recommended. Pain management (analgesic): Oral, regular release: 30 mg every 4-6 hours as needed; patients with prior opiate exposure may require higher initial doses. Usual range: mg every 4-6 hours as needed Pain management (analgesic): Oral, regular release: 30 mg every 4-6 hours as needed; patients with prior opiate exposure may require higher initial doses. Usual range: mg every 4-6 hours as needed Oral, controlled release formulation (Codeine Contin®, not available in U.S.): mg every 12 hours. I.M., SubQ: 30 mg every 4-6 hours as needed; patients with prior opiate exposure may require higher initial doses. Usual range: mg every 4-6 hours as needed; more frequent dosing may be needed Cough (antitussive): Oral (for nonproductive cough): mg/dose every 4-6 hours as needed; maximum: 120 mg/day

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26 26 Codeina DOSING: PEDIATRIC DOSING: PEDIATRIC Analgesic: Oral, I.M., SubQ: –Children: mg/kg/dose every 4-6 hours as needed; maximum: 60 mg/dose Antitussive: Oral (for nonproductive cough): –Children: mg/kg/day in divided doses every 4-6 hours as needed: –Alternative dose according to age: 2-6 years: mg every 4-6 hours as needed; maximum: 30 mg/day 6-12 years: 5-10 mg every 4-6 hours as needed; maximum: 60 mg/day

27 27 Codeina DOSING: HEPATIC IMPAIRMENT Dosing adjustment is probably necessary in hepatic insufficiency.

28 28 Dosis de carga Dosis de manteni miento FG > 50 ml/min FG ml/min FG < 10 ml/min Dosis suplemta ria tras HD DPCATSCR Codeina 100 % 75%50% Descono -cida Desono- cida 75% Vida media de eliminación prolongada en pacientes en diálisis.

29 29 Codeina ADVERSE REACTIONS SIGNIFICANT Frequency not defined: AST/ALT increased >10%: Central nervous system: Somnolencia Gastrointestinal: Estreñimiento 1% to 10%: Cardiovascular: Tachycardia or bradycardia, hypotension Central nervous system: Dizziness, lightheadedness, false feeling of well being, malaise, headache, restlessness, paradoxical CNS stimulation, confusion Dermatologic: Rash, urticaria Gastrointestinal: Dry mouth, anorexia, nausea, vomiting Genitourinary: Urination decreased, ureteral spasm Hepatic: LFTs increased Local: Burning at injection site Neuromuscular & skeletal: Weakness Ocular: Blurred vision Respiratory: Dyspnea Miscellaneous: Histamine release <1% (Limited to important or life-threatening): Convulsions, hallucinations, insomnia, mental depression, nightmares

30 30 Codeina DRUG INTERACTIONS Substrate of CYP2D6 (major), 3A4 (minor); Inhibits CYP2D6 (weak) CYP2D6 inhibitors: May decrease the effects of codeine. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole. Decreased effect with cigarette smoking Increased toxicity: CNS depressants, phenothiazines, TCAs, other narcotic analgesics, guanabenz, MAO inhibitors, neuromuscular blockers

31 31 Codeina Embarazo y Lactancia. –Contraindicado.

32 32 Codeina REFERENCE RANGE REFERENCE RANGE –Therapeutic: Not established; –Toxic: >1.1 mcg/mL Sobredosis: –Symptoms include CNS and respiratory depression, gastrointestinal cramping, and constipation. –Treatment includes naloxone 2 mg I.V. (0.01 mg/kg for children), with repeat administration as necessary, up to a total of 10 mg.

33 33Codeina PHARMACODYNAMICS / KINETICS Onset of action: Oral: hour; I.M.: minutes Peak effect: Oral: hours; I.M.: hour Duration: 4-6 hours Absorption: Oral: Adequate Las propiedades farmacocinéticas de la codeína le confieren una aceptable biodisponibilidad oral (50%), lo que permite su administración (casi exclusiva) por esta vía. Distribution: Crosses placenta; enters breast milk Protein binding: 7% Metabolism: Hepatic to morphine (active) 10% de codeina se metaboliza a morfina. Half-life elimination: hours. Su baja semivida de eliminación obliga a la administración cada 4-6 h, lo que ha llevado a la comercialización de algunos derivados, como la dihidrocodeína, en forma de preparados de liberación sostenida, especialmente indicadas en situaciones de dolor crónico Excretion: Urine (3% to 16% as unchanged drug, norcodeine, and free and conjugated morphine)

34 34 N02A-Analgésicos narcóticos (Opioides) NOMBRE GENÉRICOPRESENTACIÓNVIANOMBRE COMERCIAL BuprenorfinaComp 0,2 mg Amp 0,3 mg/1 ml SL IM, IV Buprex CE CodeínaComp 28 mgORCodeisan Dihidrocodeína (Hidrocodona) Comp 60 mgORContugesic Fentanilo (2)Parche 2,5 mg (3) Parche 5 mg (3) Parche 10 mg (3) TOP Durogesic 25 Durogesic 50 Durogesic 100 MetadonaAmp 10 mg/1 ml Comp 5 mg Comp 40 mg SC, IM OR Metasedin CE Morfina cloruroAmp 10 mg/1 ml (sin conservantes) Vial 400 mg/20 ml (vial multidosis, sin conservantes) Amp 10 ml. SC, IV, IM SC IV, IM Cloruro Mórfico Braun 1 % CE Morfina Braun 2 % s/c CE Morfina Braun 4 % s/c CE Morfina clorhidratoJbe 10 mg/mlORBrompton FM CE Morfina sulfatoComp 10 mg Comp 20 mg OR Sevredol CE (1) Morfina sulfato retardComp 10 mg Comp 30 mg Comp 60 mg Comp 100 mg OR MST Continus CE Petidina (Meperidina)Amp 100 mg/2 mlSC, IM, IVDolantina CE TramadolCaps 50 mg Comp retard 200 mg Comp retard 300 mg Amp 100 mg/2 m OR SC, IM, IV Adolonta, Tralgiol Zytram CE: Control de estupefacientes. Nota 1: Comprimidos ranurados. Nota 2: Uso restringido para tratamiento del dolor crónico. Nota 3: Los parches de 2,5, 5 y 10 mg liberan respectivamente 25, 50 y 100 mcg/h durante 72 h.

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36 36 Tramadol Análogo sintético de codeina. Analgésico no narcótico de acción periférico y central.

37 37 Tramadol Mecanismo de acción: –Inhibición de la recaptación de NA y serotonina por las celulas nerviosas. –Actúa sobre los receptores opioides Mu.

38 38 N02A-Analgésicos narcóticos (Opioides) NOMBRE GENÉRICO PRESENTACIÓNVIANOMBRE COMERCIAL TramadolCaps 50 mg Comp retard 200 mg Comp retard 300 mg Amp 100 mg/2 ml OR SC, IM, IV Adolonta, Tralgiol Zytram

39 39TramadolPRESENTACIONES: –Adolonta amp de 100 mg en 2 ml –Tralgiol amp de 100 mg en 2 ml ADMINISTRACION: –INYECCION IV DIRECTA: SI –Administrar lentamente. –INFUSION INTERMITENTE: SI Diluir la dosis prescrita en ml de SF o SG5%. Administrar en minutos. –INFUSION CONTINUA: SI Diluir la dosis prescrita, ejemplo 2 amp en 500 ml de SF o SG5%. El ritmo de infusión adecuado es de gotas/min ó ml/h que equivalen a mg/h de Tramadol. –INYECCION IM: SI –INYECCION SUBCUTANEA: SI SUEROS COMPATIBLES: SF, SG5%. OBSERVACIONES: –La dosificacion máxima diaria en adultos por cualquier vía es de 400 mg/día. –También se dispone de estudios de administración vía epidural.

40 40 Tramadol DOSING: ADULTS Moderate-to-severe chronic pain: Oral: – –Caps 50 mg mg every 4-6 hours (not to exceed 400 mg/day) For patients not requiring rapid onset of effect, tolerability may be improved by starting dose at 25 mg/day and titrating dose by 25 mg every 3 days, until reaching 25 mg 4 times/day. Dose may then be increased by 50 mg every 3 days as tolerated, to reach dose of 50 mg 4 times/day. – –Comp retard 200 mg. Comp retard 300 mg 100 mg once daily; titrate every 5 days (maximum: 300 mg/day)

41 41 Tramadol DOSING: ELDERLY Oral: >75 years: – –Caps 50 mg 50 mg every 6 hours (not to exceed 300 mg/day – –Comp retard 200 mg. Comp retard 300 mg 100 mg once daily; titrate every 5 days (maximum: 300 mg/day). Use with great caution.

42 42 Tramadol DOSING: RENAL IMPAIRMENT –Clcr <30 mL/minute: mg dose every 12 hours (maximum: 200 mg/day). –Should not be used in patients with Clcr < 30 mL/minute. DOSING: HEPATIC IMPAIRMENT –Cirrhosis: Recommended dose: 50 mg every 12 hours. –Should not be used in patients with severe (Child- Pugh Class C) hepatic dysfunction.

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44 44 Tramadol Efectos secundarios: >10%: Cardiovascular: Flushing (8% to 16%) Central nervous system: mareos (16% to 33%), headache (8% to 32%), insomnia (7% to 11%), somnolence (7% to 25%) Dermatologic: Pruritus (6% to 12%) Gastrointestinal: Constipation (12% to 46%), nausea (15% to 40%) Neuromuscular & skeletal: Weakness (4% to 12%)

45 45 Tramadol Efectos secundarios: 1% to 10%: Cardiovascular: Chest pain (1% to <5%), postural hypotension (2% to 5%), vasodilation (1% to <5%) Central nervous system: Agitation, anxiety (1% to <5%), confusion (1% to <5%), coordination impaired (1% to <5%), depression (1% to <5%), emotional lability, euphoria, hallucinations, hypoesthesia, lethargy, malaise, nervousness (1% to <5%), pain, pyrexia, restlessness Dermatologic: Dermatitis, rash Endocrine & metabolic: Hot flashes (2% to 9%), menopausal symptoms (1% to <5%) Gastrointestinal: Abdominal pain, anorexia (<6%), diarrhea (5% to 10%), dry mouth (5% to 10%), dyspepsia, flatulence, vomiting (5% to 9%), weight loss Genitourinary: Urinary frequency (1% to <5%), urinary retention (1% to <5%), urinary tract infection (1% to <5%) Neuromuscular & skeletal: Arthralgia (1% to <5%), hypertonia (1% to <5%), rigors (<4%), paresthesia (1% to <5%), spasticity (1% to <5%), tremor (1% to <5%), creatinine phosphokinase increased Ocular: Blurred vision (1% to <5%), miosis (1% to <5%) Respiratory: Bronchitis (1% to <5%), cough (1% to <5%), dyspnea (1% to <5%), pharyngitis (1% to <5%), rhinorrhea (1% to <5%), sinusitis (1% to <5%) Miscellaneous: Diaphoresis (2% to 6%), flu-like syndrome (<2%)

46 46 Tramadol El tramadol presenta una baja o nula capacidad para causar cuadros de farmacodependencia. Epileptógeno en situaciones con disminución del umbral de epilepsia (uremia, tumores cerebrales)

47 47 Tramadol DRUG INTERACTIONS Substrate of CYP2B6 (minor), 2D6 (major), 3A4 (minor) Carbamazepine: Tramadol metabolism is increased by carbamazepine. Avoid concurrent use; increases risk of seizures. Cyclobenzaprine: May enhance the neuroexcitatory and/or seizure-potentiating effect of tramadol. CYP2D6 inhibitors: May decrease the effects of tramadol. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole. Ethanol: Tramadol may enhance the CNS depressant effect of ethanol. MAO inhibitors: May increase the neuroexcitatory effects or risk of seizures. Examples of inhibitors include isocarboxazid, linezolid, phenelzine, selegiline, and tranylcypromine. Naloxone: May increase the risk of seizures (if administered in tramadol overdose). Quinidine: May increase the tramadol serum concentrations and decrease serum concentrations of M1 SSRIs: May increase the neuroexcitatory effects or risk of seizures with tramadol. Examples of SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline. Serotonin modulators: May enhance the adverse/toxic effects of tramadol. The development of serotonin syndrome may occur. Sibutramine: May enhance the serotonergic effects of tramadol. Avoid concurrent use. Tricyclic antidepressants: May increase the risk of seizures.

48 48 Tramadol Embarazo y lactancia. –Contraindicado. –Atraviesa la placenta. –Aparece en la leche materna.

49 49 Tramadol Rango terapéutico: – ng/mL

50 50 Tramadol Sobredosis: –Clínica: Depresión del SNC, depresion respiratoria, letargia, coma, miosis, convulsiones, fallo cardíaco y muerte. –Tratamiento sintomático. –La administración de naloxona no revierte completamente los efectos del tramadol, y puede aumentar el riesgo de convulsiones. –No se elimina mediante Hemodiálisis.

51 51TramadolFarmacocinética: –Inicio de acción en 1 horas. –Duración de acción 9 horas. –Absorción oral rápida y completa. –VD 2,5-3 l/kg. –Unión aproteinas plasmáticas: 20%. –Metabolismo: Hepatico (demethylation, glucuronidation, and sulfation) Metabolito activo (O-desmethyl tramadol) Vida media de eliminación: Prolongada en ancianos, daño hepático y renal (en esta última X2). –Tramadol: 6-8 horas.(obliga a su administración varias veces al día). –O-desmethyl tramadol: 7-9 horas. Excreccion: Urinaria (30% como fármaco; 60% como metabolito)

52 52 Dosis de carga Dosis de manteni miento FG > 50 ml/min FG ml/min FG < 10 ml/min Dosis suplemta ria tras HD DPCATSCR Tramadol Clcr <30 mL/minute: mg dose every 12 hours (maximum: 200 mg/day). Should not be used in patients with Clcr < 30 mL/minute.

53 53

54 54 Oxicodona Agonista puro. Se comercializa como medicamento de liberación controlada (OxyContin) o de liberación rápida (OxyIR, OxyNorm). –El OxyContin se presenta en comprimidos de 10, 20, 40 y 80 mg, y debido a su mecanismo de liberación lenta, es efectivo durante unas doce horas. –Oxynorm caps. 5, 10 y 20 mg –OXYNORM Concentrado 10 mg/ml solución oral –OXYNORM Líquido 1 mg/ 1 ml sol.oral

55 55Oxicodona DOSING: ADULTS Management of pain: Oral: Regular or immediate release formulations: mg every 6 hours Controlled release: Opioid naive (not currently on opioid): 10 mg every 12 hours Currently on opioid/ASA or acetaminophen or NSAID combination: 1-5 tablets: mg every 12 hours 6-9 tablets: mg every 12 hours tablets: mg every 12 hours May continue the nonopioid as a separate drug. Currently on opioids: Use standard conversion chart to convert daily dose to oxycodone equivalent. Divide daily dose in 2 (for every 12-hour dosing) and round down to nearest dosage form. Note: 80 mg or 160 mg tablets are for use only in opioid-tolerant patients. Special safety considerations must be addressed when converting to OxyContin® doses 160 mg every 12 hours. Dietary caution must be taken when patients are initially titrated to 160 mg tablets.

56 56 Oxicodona DOSING: PEDIATRIC Oral: Regular or immediate release formulations: –6-12 years: 1.25 mg every 6 hours as needed –>12 years: 2.5 mg every 6 hours as needed

57 57 Oxicodona DOSING: HEPATIC IMPAIRMENT Reduce dosage in patients with severe liver disease. DOSING: RENAL IMPAIRMENT – Se prolonga la vida media de eliminación. Relacionado con casos de GNF fibrilar

58 58Oxicodona ADVERSE REACTIONS SIGNIFICANT >10%: Central nervous system: Fatigue, drowsiness, dizziness, somnolence Dermatologic: Pruritus Gastrointestinal: Nausea, vomiting, constipation Neuromuscular & skeletal: Weakness 1% to 10%: Cardiovascular: Postural hypotension Central nervous system: Nervousness, headache, restlessness, malaise, confusion, anxiety, abnormal dreams, euphoria, thought abnormalities Dermatologic: Rash Gastrointestinal: Anorexia, stomach cramps, xerostomia, biliary spasm, abdominal pain, dyspepsia, gastritis Genitourinary: Ureteral spasms, decreased urination Local: Pain at injection site Respiratory: Dyspnea, hiccups Miscellaneous: Diaphoresis <1% (Limited to important or life-threatening): Anaphylaxis, anaphylactoid reaction, dysphagia, exfoliative dermatitis, hallucinations, histamine release, hyponatremia, ileus, intracranial pressure increased, mental depression, paradoxical CNS stimulation, paralytic ileus, physical and psychological dependence, SIADH, syncope, urinary retention, urticaria, vasodilation, withdrawal syndrome (may include seizure) Note: Deaths due to overdose have been reported due to misuse/abuse after crushing the sustained release tablets.

59 59 Oxicodona CONTRAINDICATIONS CONTRAINDICATIONS Hypersensitivity to oxycodone or any component of the formulation; Significant respiratory depression; hypercarbia; acute or severe bronchial asthma; OxyContin® is also contraindicated in paralytic ileus (known or suspected); pregnancy (prolonged use or high doses at term)

60 60Oxicodona Use with caution in the elderly, debilitated, severe hepatic or renal function. Hemodynamic effects (hypotension, orthostasis) may be exaggerated in patients with hypovolemia, concurrent vasodilating drugs, or in patients with head injury. Respiratory depressant effects and capacity to elevate CSF pressure may be exaggerated in presence of head injury, other intracranial lesion, or pre-existing intracranial pressure. Some preparations contain sulfites which may cause allergic reactions.

61 61 Oxicodona DRUG INTERACTIONS Substrate of CYP2D6 (major) CNS depressants, MAO inhibitors, general anesthetics, and tricyclic antidepressants: May potentiate the effects of opiate agonists; dextroamphetamine may enhance the analgesic effect of opiate agonists CYP2D6 inhibitors: May decrease the effects of oxycodone. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

62 62 Oxicodona Embarazo: –Contraindicado. Lactancia: –Pasa a la leche materna. Usar con precaución.

63 63 Oxicodona PHARMACODYNAMICS / KINETICS Onset of action: minutes. Peak effect: hour Duration: 3-6 hours; –Controlled release: 12 hours Metabolism: Hepatic (noroxycodona y oxymorfona) Half-life elimination: 2-3 hours Excretion: Urine (10% como fármaco)

64 64 Dosis de carga Dosis de manteni miento FG > 50 ml/min FG ml/min FG < 10 ml/min Dosis suplemta ria tras HD DPCATSCR Oxicodona

65 65

66 66 N02A-Analgésicos narcóticos (Opioides) NOMBRE GENÉRICO PRESENTACIÓNVIANOMBRE COMERCIAL Fentanilo (2)Parche 2,5 mg (3) Parche 5 mg (3) Parche 10 mg (3) TOP Durogesic 25 Durogesic 50 Durogesic 100 CE: Control de estupefacientes. Nota 2: Uso restringido para tratamiento del dolor crónico. Nota 3: Los parches de 2,5, 5 y 10 mg liberan respectivamente 25, 50 y 100 mcg/h durante 72 h. Actiq®: 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, 1600 mcg Actiq®: 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, 1600 mcg

67 67 Fentanilo Mecanismo de acción: Mecanismo de acción: Agonistas de los tres receptores opioides. Se caracteriza por su elevada potencia farmacológica, muy por encima de la morfina, su elevada liposolubilidad, y su escasa biodisponibilidad tras la administración oral. Inidicaciones: –Parche transdérmico (Duragesic®): Tratamiento del dolor crónico moderado o severo. –Transmucosal (Actiq®): Tratamiento del dolor irruptivo. (evita el primer paso hepático)

68 68 Fentanilo Chronic pain management: –Dosis inicial 25 mcg/h si el paciente no toma morfina o toma menos de 90 mg/dia.

69 69 Fentanilo Dose conversion guidelines for transdermal fentanyl 1. Recommended Initial Duragesic® Dose Based Upon Daily Oral Morphine Dose1 – mg morphine oral/day = 25 mcg/hour Duragesic® – mg morphine oral/day = 50 mcg/hour Duragesic® – mg morphine oral/day = 75 mcg/hour Duragesic® – mg morphine oral/day = 100 mcg/hour Duragesic® – mg morphine oral/day = 125 mcg/hour Duragesic® – mg morphine oral/day = 150 mcg/hour Duragesic® – mg morphine oral/day = 175 mcg/hour Duragesic® – mg morphine oral/day = 200 mcg/hour Duragesic® – mg morphine oral/day = 225 mcg/hour Duragesic® – mg morphine oral/day = 250 mcg/hour Duragesic® – mg morphine oral/day = 275 mcg/hour Duragesic® – mg morphine oral/day = 300 mcg/hour Duragesic®

70 70 Dosing Conversion Guidelines1,2 Morphine (I.M./I.V.): mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour Oxycodone (oral): mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour Oxycodone (I.M./I.V.): mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour Codeine (oral): mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour

71 71 Dosing Conversion Guidelines1,2 Hydromorphone (oral): 8-17 mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour 8-17 mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour Hydromorphone (I.M./I.V.): mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour 8-10 mg/day: recommended fentanyl transdermal dose: 100 mcg/hour mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour 8-10 mg/day: recommended fentanyl transdermal dose: 100 mcg/hour Meperidine (I.M.): mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour

72 72 Dosing Conversion Guidelines1,2 Methadone (oral): mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour Methadone (I.M.): mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour mg/day: recommended fentanyl transdermal dose: 25 mcg/hour mg/day: recommended fentanyl transdermal dose: 50 mcg/hour mg/day: recommended fentanyl transdermal dose: 75 mcg/hour mg/day: recommended fentanyl transdermal dose: 100 mcg/hour 1The table should NOT be used to convert from transdermal fentanyl (eg, Duragesic®) to other opioid analgesics. Rather, following removal of the patch, titrate the dose of the new opioid until adequate analgesia is achieved.

73 73 Fentanilo Breakthrough cancer pain: Transmucosal: Actiq® dosing should be individually titrated to provide adequate analgesia with minimal side effects. For patients who are tolerant to and currently receiving opioid therapy for persistent cancer pain. Initial starting dose: 200 mcg; the second dose may be started 15 minutes after completion of the first dose. Consumption should be limited to 4 units/day or less. Patients needing more than 4 units/day should have the dose of their long-term opioid re-evaluated.

74 74 Fentanilo DOSING: PEDIATRIC –Breakthrough cancer pain: Children 16 years: Transmucosal: Refer to adult dosing. –Chronic pain management: Children 2 years (opioid- tolerant patients): Transdermal patch: Refer to adult dosing.

75 75 Fentanilo DOSING: ELDERLY DOSING: ELDERLY –Elderly have been found to be twice as sensitive as younger patients to the effects of fentanyl. –A wide range of doses may be used. When choosing a dose, take into consideration the following patient factors: age, weight, physical status, underlying disease states, other drugs used, type of anesthesia used, and the surgical procedure to be performed. –Transmucosal: Dose should be reduced to mcg/kg. Suck on lozenge vigorously approximately minutes before the start of procedure.

76 76 Fentanilo Transdermal patch (eg, Duragesic®): –Apply to nonirritated and nonirradiated skin, such as chest, back, flank, or upper arm. –Do not shave skin; hair at application site should be clipped. –Prior to application, clean site with clear water and allow to dry completely. –Do not use damaged or cut patches; a rapid release of fentanyl and increased systemic absorption may occur. Firmly press in place and hold for 30 seconds. –Change patch every 72 hours. –Do not use soap, alcohol, or other solvents to remove transdermal gel if it accidentally touches skin; use copious amounts of water. –Avoid exposing application site to external heat sources (eg, heating pad, electric blanket, heat lamp, hot tub).

77 77 Fentanilo Transmucosal: Foil overwrap should be removed just prior to administration. Place the unit in mouth and allow it to dissolve. Do not chew. Actiq® units may be moved from one side of the mouth to the other. The unit should be consumed over a period of 15 minutes. Unit should be removed after it is consumed or if patient has achieved an adequate response and/or shows signs of respiratory depression. For patients who have received transmucosal product within 6-12 hours, it is recommended that if other narcotics are required, they should be used at starting doses 1/4 to 1/3 those usually recommended.

78 78 Fentanilo ADVERSE REACTIONS SIGNIFICANT >10%: Cardiovascular: Hypotension, bradycardia Central nervous system: CNS depression, confusion, drowsiness, sedation Gastrointestinal: Nausea, vomiting, constipation, xerostomia Local: Application-site reaction (iontophoretic system 14%) Neuromuscular & skeletal: Chest wall rigidity (high dose I.V.), weakness Ocular: Miosis Respiratory: Respiratory depression Miscellaneous: Diaphoresis

79 79 Fentanilo ADVERSE REACTIONS SIGNIFICANT 1% to 10%: Cardiovascular: Cardiac arrhythmia, edema, orthostatic hypotension, hypertension, syncope, tachycardia Central nervous system: Abnormal dreams, abnormal thinking, agitation, amnesia, anxiety, dizziness, euphoria, fatigue, fever, hallucinations, headache, insomnia, nervousness, paranoid reaction Dermatologic: Erythema, papules, pruritus (iontophoretic system 6%), rash Gastrointestinal: Abdominal pain, anorexia, biliary tract spasm, diarrhea, dyspepsia, flatulence, ileus Genitourinary: Urinary retention (iontophoretic transdermal system 3%) Hematologic: Anemia Neuromuscular & skeletal: Abnormal coordination, abnormal gait, back pain, paresthesia, rigors, tremor Respiratory: Apnea, bronchitis, dyspnea, hemoptysis, hypoxia, pharyngitis, rhinitis, sinusitis, upper respiratory infection Miscellaneous: Hiccups, flu-like syndrome, speech disorder <1% (Limited to important or life-threatening): Amblyopia, anorgasmia, aphasia, bradycardia, bronchospasm, circulatory depression, CNS excitation or delirium, convulsions, dental caries (Actiq®), depersonalization, dysesthesia, ejaculatory difficulty, exfoliative dermatitis, gum line erosion (Actiq®), hyper-/hypotonia, laryngospasm, paradoxical dizziness, physical and psychological dependence with prolonged use, stertorous breathing, stupor, tachycardia, tooth loss (Actiq®), urinary tract spasm, urticaria, vertigo

80 80 Fentanilo CONTRAINDICATIONS Hypersensitivity to fentanyl or any component of the formulation; increased intracranial pressure; severe respiratory disease or depression including acute asthma (unless patient is mechanically ventilated); paralytic ileus; severe liver or renal insufficiency; pregnancy (prolonged use or high doses near term) Transmucosal lozenges (Actiq®) or transdermal patches (eg, Duragesic®) must not be used in patients who are not opioid tolerant. Patients are considered opioid-tolerant if they are taking at least 60 mg morphine/day, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mcg transdermal fentanyl/hour, or an equivalent dose of another opioid for 1 week. Transdermal patches are not for use in acute pain, mild pain, intermittent pain, or postoperative pain management.

81 81 Fentanilo Transdermal patches (eg, Duragesic®): Serious or life-threatening hypoventilation may occur, even in opioid-tolerant patients. Serum fentanyl concentrations may increase approximately one-third for patients with a body temperature of 40ºC secondary to a temperature-dependent increase in fentanyl release from the patch and increased skin permeability. Avoid exposure of application site to direct external heat sources. Patients who experience adverse reactions should be monitored for at least 24 hours after removal of the patch. Transdermal patch does not contain any metal-based compounds; the printed ink used to indicate strength on the outer surface of the patch does contain titanium dioxide but the amount is minimal; adverse events have not been reported while wearing during an MRI. Safety and efficacy of transdermal patch have been limited to children 2 years of age who are opioid tolerant.

82 82 Fentanilo Actiq®: For patients who have received transmucosal product within 6-12 hours, it is recommended that if other narcotics are required, they should be used at starting doses 1/4 to 1/3 those usually recommended. Actiq® preparations contain an amount of medication that can be fatal to children. Keep all units out of the reach of children and discard any open units properly. Patients and caregivers should be counseled on the dangers to children including the risk of exposure to partially-consumed units. Safety and efficacy have not been established in children <16 years of age.

83 83 Fentanilo DRUG INTERACTIONS Substrate of CYP3A4 (major); Inhibits CYP3A4 (weak) Antipsychotic agents (phenothiazines): May enhance the hypotensive effect of analgesics (narcotic). CNS depressants: Increased sedation with CNS depressants.; CYP3A4 inhibitors: May increase the levels/effects of fentanyl. Potentially fatal respiratory depression may occur when a potent inhibitor is used in a patient receiving chronic fentanyl (eg, transdermal patch). Example inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil. MAO inhibitors: Not recommended to use Actiq® within 14 days. Severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Pegvisomant: Analgesics (narcotic) may diminish the therapeutic effect of pegvisomant. Protease inhibitors: May decrease the metabolism, via CYP isoenzymes, of fentanyl. Selective serotonin reuptake inhibitors (SSRIs): Analgesics (narcotic) may enhance the serotonergic effect of SSRIs. This may cause serotonin syndrome. Sibutramine: Fentanyl may enhance the serotonergic effect of sibutramine.

84 84 Fentanilo Embarazo: –Su uso de forma crónica puede producir dependencia en el recien nacido. –De forma aguda cruza la placenta pero se ha utilizado de forma segura durante el trabajo del parto. Lactancia: Pasa a la leche materna. No recomendado.

85 85 Fentanilo MONITORING PARAMETERS Control de la función respiratoria y cardiovascular, Tensión arterial y frecuencia cardíaca. Transdermal patch: Monitorizar a las 24 horas de la aplicación del parche.

86 86 Fentanilo Sobredosis: Síntomas: depresión del SNC, depresión respiratoria, miosis. Tratamiento: –De soporte. –Naloxone, 2 mg I.V. with repeat administration as necessary up to a total of 10 mg, can also be used to reverse toxic effects of the opiate. Los pacientes que presentan reacciones adversas durante el uso del parche transdérmico deben ser monitorizados durante 24 horas tras la retirada del parche.

87 87 Fentanilo Farmacocinética: Onset of action: –Transmucosal: 5-15 minutes –Peak effect: Transmucosal: Analgesic: minutes –Time to peak: Transdermal patch: hours Absorption: Transmucosal: Rapid, ~25% from the buccal mucosa; 75% swallowed with saliva and slowly absorbed from GI tract Actiq® contains 2 g sugar per unit. Distribution: Highly lipophilic, redistributes into muscle and fat Metabolism: Hepatic, primarily via CYP3A4 Bioavailability: Transmucosal: ~50% (range: 36% to 71%) Half-life elimination: 2-4 hours Transdermal patch: 17 hours (half-life is influenced by absorption rate) Transmucosal: 6.6 hours (range: 5-15 hours) Excretion: Urine (primarily as metabolites, 10% as unchanged drug)

88 88 Dosis de carga Dosis de manteni miento FG > 50 ml/min FG ml/min FG < 10 ml/min Dosis suplemta ria tras HD DPCATSCR Fentanilo100%75%50% No aplicable Su aclaramiento se reduce en pacientes con ERC avanzada, pudiendo aparecer sedación prologada y depresion respiratoria en pacientes con ERC avanzada. (sobre todo en administración parenteral).

89 89

90 90 Morfina Alcaloide de la Papaver somniferum. Sigue constituyendo el analgésico más potente del que se dispone para tratar todo tipo de dolores agudos y muchos de los crónicos. Modelo de agonista puro de los receptores opioides. Actúa activando los tres receptores opioides.

91 91 N02A-Analgésicos narcóticos (Opioides) NOMBRE GENÉRICOPRESENTACIÓNVIANOMBRE COMERCIAL Morfina cloruroAmp 10 mg/1 ml (sin conservantes) Vial 400 mg/20 ml (vial multidosis, sin conservantes) Amp 10 ml. SC, IV, IM SC IV, IM Cloruro Mórfico Braun 1 % CE Morfina Braun 2 % s/c CE Morfina Braun 4 % s/c CE Morfina clorhidratoJbe 10 mg/mlORBrompton FM CE Morfina sulfatoComp 10 mg Comp 20 mg OR Sevredol CE (1) Morfina sulfato retardComp 10 mg Comp 30 mg Comp 60 mg Comp 100 mg OR MST Continus CE CE: Control de estupefacientes. Nota 1: Comprimidos ranurados. Nota 2: Uso restringido para tratamiento del dolor crónico. Nota 3: Los parches de 2,5, 5 y 10 mg liberan respectivamente 25, 50 y 100 mcg/h durante 72 h.

92 92MorfinaADMINISTRACION: INYECCION IV DIRECTA: SI –Administrar la dosis precrita muy lentamente. Diluir la dosis en 4-5 ml de agua p.i. antes de administrar. La administración rápida aumenta el riesgo de aparición de efectos secundarios (depresión respiratoria, apnea, hipotensión). INFUSION INTERMITENTE: SI –Diluir la dosis prescrita en ml de SF ó SG5%. INFUSION CONTINUA: SI –Diluir la dosis prescrita en ml de SF ó SG5%. INYECCION IM: SI –Esta vía es preferible sobre la vía subcutánea cuando deben administrarse dosis repetidas. Aunque la absorción es más irregular y la duración de acción menor que si se usa la vía sc. INYECCION SUBCUTANEA: SI –La absorción es más lenta que por vía IM, pero la analgesia suele ser más constante y duradera. SUEROS COMPATIBLES: SF, SG5% OBSERVACIONES: –El preparado sin conservante también se puede administrar via epidural e intratecal.

93 93 Morfina DOSING: ADULTS DOSING: ADULTS Acute pain (moderate-to-severe): Oral: Prompt release formulations: Opiate-naive: Initial: 10 mg every 3 to 4 hours as needed; patients with prior opiate exposure may require higher initial doses: usual dosage range: mg every 3-4 hours as needed Oral: Prompt release formulations: Opiate-naive: Initial: 10 mg every 3 to 4 hours as needed; patients with prior opiate exposure may require higher initial doses: usual dosage range: mg every 3-4 hours as needed I.M., SubQ:. Initial: Opiate-naive: 5-10 mg every 3-4 hours as needed; patients with prior opiate exposure may require higher initial doses; usual dosage range: 5-20 mg every 3-4 hours as needed I.M., SubQ:. Initial: Opiate-naive: 5-10 mg every 3-4 hours as needed; patients with prior opiate exposure may require higher initial doses; usual dosage range: 5-20 mg every 3-4 hours as needed Rectal: mg every 3-4 hours I.V.: Initial: Opiate-naive: mg every 3 to 4 hours; patients with prior opiate exposure may require higher initial doses. Note: Repeated doses (up to every 5 minutes if needed) in small increments (eg, 1-4 mg) may be preferred to larger and less frequent doses. I.V.: Initial: Opiate-naive: mg every 3 to 4 hours; patients with prior opiate exposure may require higher initial doses. Note: Repeated doses (up to every 5 minutes if needed) in small increments (eg, 1-4 mg) may be preferred to larger and less frequent doses.

94 94

95 95 Morfina DOSING: PEDIATRIC DOSING: PEDIATRIC –Acute pain (moderate-to-severe): Children >6 months and 6 months and <50 kg: Oral (prompt release): mg/kg every 3-4 hours as needed I.M.: 0.1 mg/kg every 3-4 hours as needed I.V.: mg/kg every 3-4 hours as needed I.V. infusion: Range: mcg/kg/hour –Sedation/analgesia for procedures: Adolescents >12 years: I.V.: 3-4 mg and repeat in 5 minutes if necessary

96 96 Morfina DOSING: ELDERLY Refer to adult dosing. Use with caution; may require reduced dosage in the elderly and debilitated patients. DOSING: RENAL IMPAIRMENT –Clcr mL/minute: Administer 75% of normal dose. –Clcr <10 mL/minute: Administer 50% of normal dose. DOSING: HEPATIC IMPAIRMENT Unchanged in mild liver disease; substantial extrahepatic metabolism may occur. Excessive sedation may occur in cirrhosis.

97 97 Morfina ADVERSE REACTIONS SIGNIFICANT ADVERSE REACTIONS SIGNIFICANT >10%: Cardiovascular: Palpitations, hypotension, bradycardia Central nervous system: Somnolencia (48%, tolerance usually develops to drowsiness with regular dosing for 1-2 weeks); mareos (20%), confusion, headache (following epidural or intrathecal use) Dermatologic: Pruritus (may be secondary to histamine release) Note: Pruritus may be dose-related, but not confined to the site of administration. Gastrointestinal: Nausea (28%, tolerance usually develops to nausea and vomiting with chronic use); constipation (40%, tolerance develops very slowly if at all); xerostomia (78%) Genitourinary: Urinary retention (16%; may be prolonged, up to 20 hours, following epidural or intrathecal use) Local: Pain at injection site Neuromuscular & skeletal: Weakness Miscellaneous: Histamine release

98 98 Morfina DRUG INTERACTIONS Substrate of CYP2D6 (minor) Antipsychotic agents: May increase hypotensive effects of morphine; monitor. CNS depressants: May increase the effects/toxicity of morphine; monitor. MAO inhibitors: May increase the effects/toxicity of morphine; some manufacturers recommend avoiding use within 14 days of MAO inhibitors Pegvisomant: Therapeutic efficacy may be decreased by concomitant opiates, possibly requiring dosage adjustment of pegvisomant. Rifamycin derivatives: May decrease levels/effects of morphine; monitor. Selective serotonin reuptake inhibitors (SSRIs) and meperidine: Serotonergic effects may be additive, leading to serotonin syndrome.

99 99 Morfina PREGNANCY IMPLICATIONS Morphine crosses the placenta. The frequency of congenital malformations has not been reported to be greater than expected in children from mothers treated with morphine during pregnancy. Reduced growth and behavioral abnormalities in offspring have been observed in animal studies. Neonates born to mothers receiving chronic opioids during pregnancy should be monitored for neonatal withdrawal syndrome. LACTATION Enters breast milk

100 100 Morfina REFERENCE RANGE REFERENCE RANGE –Therapeutic: Surgical anesthesia: ng/mL (SI: nmol/L); –Toxic: ng/mL (SI: ,500 nmol/L) TOXICOLOGY / OVERDOSE COMPREHENSIVE TOXICOLOGY / OVERDOSE COMPREHENSIVE Symptoms include respiratory depression, miosis, hypotension, bradycardia, apnea, and pulmonary edema. Treatment includes –airway support, –establishment of an I.V. line, and –administration of naloxone 2 mg I.V. (0.01 mg/kg for children), with repeat administration as necessary, up to a total of 10 mg. –Primary attention should be directed to ensuring adequate respiratory exchange.

101 101 Morfina PHARMACODYNAMICS / KINETICS Onset of action: –Oral (immediate release): ~30 minutes; –I.V.: 5-10 minutes Duration: Pain relief: Immediate release formulations: 4 hours Extended release epidural injection (DepoDur): >48 hours Absorption: Variable Distribution: Vd: 3-4 L/kg; binds to opioid receptors in the CNS and periphery (eg, GI tract) Protein binding: 30% to 35%

102 102 Morfina PHARMACODYNAMICS / KINETICS Metabolism: Hepatic via conjugation with glucuronic acid to morphine-3-glucuronide (inactive), morphine-6-glucuronide (active), and in lesser amounts, morphine-3-6-diglucuronide; other minor metabolites include normorphine (active) and the 3-ethereal sulfate Bioavailability: Oral: 17% to 33% (first-pass effect limits oral bioavailability oral; parenteral effectiveness reportedly varies from 1:6 in opioid naive patients to 1:3 with chronic use) Half-life elimination: Adults: 2-4 hours (immediate release forms) Time to peak, plasma: Kadian®: ~10 hours

103 103 Morfina PHARMACODYNAMICS / KINETICS Excretion: Urine (primarily as morphine-3-glucuronide, ~2% to 12% excreted unchanged); feces (~7% to 10%). It has been suggested that accumulation of morphine-6- glucuronide might cause toxicity with renal insufficiency. All of the metabolites (ie, morphine-3-glucuronide, morphine-6- glucuronide, and normorphine) have been suggested as possible causes of neurotoxicity (eg, myoclonus).

104 104 Dosis de carga Dosis de manteni miento FG > 50 ml/min FG ml/min FG < 10 ml/min Dosis suplemta ria tras HD DPCATSCR Morfina100%75%50%Ninguna Descono- cida Dosis FG 10-50%

105 105 Buprenorfina Agonista parcial. Ello significa que la activación del receptor opioide mu por la buprenorfina a dosis máximas no consigue alcanzar los efectos máximos de la morfina. Presenta una intensa unión al receptor opioide, lo que tiene repercusiones en el tratamiento de la intoxicación aguda Presenta una intensa unión al receptor opioide, lo que tiene repercusiones en el tratamiento de la intoxicación aguda Efecto máximo inferior al de morfina o fentanilo, pero difícil de revertir con antagonistas puros.

106 106 Buprenorfina Cuando se administra buprenorfina a pacientes que están recibiendo agonistas puros, puede producirse un cierto grado de antagonismo funcional que, incluso, puede producir un cierto síndrome de abstinencia.

107 107 N02A-Analgésicos narcóticos (Opioides) NOMBRE GENÉRICOPRESENTACIÓNVIANOMBRE COMERCIAL BuprenorfinaComp 0,2 mg Amp 0,3 mg/1 ml SL IM, IV Buprex CE MetadonaAmp 10 mg/1 ml Comp 5 mg Comp 40 mg SC, IM OR Metasedin CE Petidina (Meperidina)Amp 100 mg/2 mlSC, IM, IVDolantina CE CE: Control de estupefacientes. Nota 1: Comprimidos ranurados. Nota 2: Uso restringido para tratamiento del dolor crónico. Nota 3: Los parches de 2,5, 5 y 10 mg liberan respectivamente 25, 50 y 100 mcg/h durante 72 h.

108 108 Buprenorfina DOSING: ADULTS DOSING: ADULTS Long-term use is not recommended Acute pain (moderate to severe): I.M.: Initial: Opiate-naive: 0.3 mg every 6-8 hours as needed; initial dose (up to 0.3 mg) may be repeated once in minutes after the initial dose if needed; usual dosage range: mg every 4-8 hours as needed Slow I.V.: Initial: Opiate-naive: 0.3 mg every 6- 8 hours as needed; initial dose (up to 0.3 mg) may be repeated once in minutes after the initial dose if needed

109 109 Buprenorfina Heroin or opiate withdrawal (unlabeled use): I.M., slow I.V.: Variable; mg every 6 hours Opioid dependence: Sublingual: Induction: Range: mg/day (doses during an induction study used 8 mg on day 1, followed by 16 mg on day 2; induction continued over 3-4 days). Treatment should begin at least 4 hours after last use of heroin or short-acting opioid, preferably when first signs of withdrawal appear. Titrating dose to clinical effectiveness should be done as rapidly as possible to prevent undue withdrawal symptoms and patient drop-out during the induction period. Maintenance: Target dose: 16 mg/day; range: 4-24 mg/day; patients should be switched to the buprenorphine/naloxone combination product for maintenance and unsupervised therapy

110 110 Buprenorfina DOSING: PEDIATRIC Acute pain (moderate to severe): Children 2-12 years: I.M., slow I.V.: 2-6 mcg/kg every 4- 6 hours Children 13 years: Refer to adult dosing. DOSING: ELDERLY Moderate to severe pain: I.M., slow I.V.: 0.15 mg every 6 hours; elderly patients are more likely to suffer from confusion and drowsiness compared to younger patients. Long-term use is not recommended.

111 111 Buprenorfina DRUG INTERACTIONS Substrate of CYP3A4 (major); Inhibits CYP1A2 (weak), 2A6 (weak), 2C19 (weak), 2D6 (weak) Cimetidine: May increase sedation from narcotic analgesics; however, histamine blockers may attenuate the cardiovascular response from histamine release associated with narcotic analgesics. CNS depressants: May produce additive respiratory and CNS depression; includes benzodiazepines, barbiturates, ethanol, and other sedatives. Respiratory and CV collapse was reported in a patient who received diazepam and buprenorphine. CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of buprenorphine. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins. CYP3A4 inhibitors: May increase the levels/effects of buprenorphine. Example inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil. Naltrexone: May antagonize the effect of narcotic analgesics; concurrent use or use within 7-10 days of injection for pain relief is contraindicated.

112 112 Buprenorfina PREGNANCY IMPLICATIONS Withdrawal has been reported in infants of women receiving buprenorphine during pregnancy. Onset of symptoms ranged from day 1 to day 8 of life, most occurring on day 1. LACTATION Enters breast milk. Not recommended

113 113 Buprenorfina TOXICOLOGY / OVERDOSE COMPREHENSIVE TOXICOLOGY / OVERDOSE COMPREHENSIVE Symptoms include CNS depression, pinpoint pupils, hypotension, and bradycardia. Treatment is supportive. –Naloxone may have limited effects in reversing respiratory depression; –Doxapram has also been used to stimulate respirations

114 114 Buprenorfina PHARMACODYNAMICS / KINETICS Onset of action: Analgesic: minutes Duration: 6-8 hours Absorption: I.M., SubQ: 30% to 40% Distribution: Vd: L/kg Protein binding: High Metabolism: Primarily hepatic; extensive first-pass effect Half-life elimination: hours Excretion: Feces (70%); urine (20% as unchanged drug)

115 115 Meperidina Existe otro tipo de opioides denominados agonistas- antagonistas, que son capaces de actuar como agonistas sobre un tipo de receptores y como antagonistas sobre otro tipo, por lo que producen respuestas imprevisibles. En pacientes que reciben agonistas puros, los agonistas-antagonistas pueden precipitar reacciones de abstinencia.

116 116 Meperidina Agonistas-antagonista. Estos fármacos tienen afinidad, variable de unos a otros, por los diferentes subtipos de receptores. En general se comportan como agonistas totales de kappa, pero como agonistas parciales, e incluso antagonistas, de receptores mu. Las consecuencias, dependen de si se ha administrado previamente un agonista total o no. En ausencia de éstos, el resultado es un efecto analgésico, resultado de la activación de receptores mu (parcial) y kappa (total). Ahora bien, si los pacientes están recibiendo un agonista total (morfina, fentanilo), el resultado será un desplazamiento del receptor y una activación parcial de éste por los agonistas-antagonistas. En consecuencia, los pacientes sentirán un grado menor de analgesia, lo que se interpreta como un antagonismo, cuando con frecuencia realmente no lo es desde un punto farmacológico estricto.

117 117 N02A-Analgésicos narcóticos (Opioides) NOMBRE GENÉRICOPRESENTACIÓNVIANOMBRE COMERCIAL BuprenorfinaComp 0,2 mg Amp 0,3 mg/1 ml SL IM, IV Buprex CE MetadonaAmp 10 mg/1 ml Comp 5 mg Comp 40 mg SC, IM OR Metasedin CE Petidina (Meperidina)Amp 100 mg/2 mlSC, IM, IVDolantina CE CE: Control de estupefacientes. Nota 1: Comprimidos ranurados. Nota 2: Uso restringido para tratamiento del dolor crónico. Nota 3: Los parches de 2,5, 5 y 10 mg liberan respectivamente 25, 50 y 100 mcg/h durante 72 h.

118 118Meperidina INYECCION IV DIRECTA: SI Administrar la dosis prescrita en forma de inyección IV lenta, para ello disolver con SF de forma que la concentración final sea 5 o 10 mg/ml. Ejemplo tomar 1 o 2 ml de la ampolla con una jeringa y completar el volumen hasta 10 ml. Administrar en 1 a 2 minutos. INFUSION INTERMITENTE: SI Diluir la dosis prescrita en ml de SF ó SG5%. Administrar según pauta médica.( Ejemplo 0,3 mg/Kg/hora). INFUSION CONTINUA: SI En ocasiones, para mantener a un paciente sedado se utiliza el llamado "coctel lítico", éste está compuesto por: Meperidina (Dolantina), Clorpromazina (Largactil) y Prometacina (Frinova). se administra en forma de infusión continua, en SF ó SG5%. INYECCION IM: SI Administrar la dosis prescrita en forma de inyección IM profunda. Es de elección especialmente en dosis múltiples se prefiere a la vía SC INYECCION SUBCUTANEA: SI Cuando deban administrarse dosis repetidas, es preferible la vía IM, ya que la vía SC es irritante de los tejidos. SUEROS COMPATIBLES: SF, SG5%

119 119 Meperidina DOSING: ADULTS DOSING: ADULTS –Not recommended for chronic pain. –In patients with normal renal function, doses of 600 mg/24 hours and use for 48 hours are recommended (American Pain Society, 1999). Pain (analgesic): I.M., SubQ: Initial: Opiate-naive: mg every 3-4 hours as needed; patients with prior opiate exposure may require higher initial doses. Pain (analgesic): I.M., SubQ: Initial: Opiate-naive: mg every 3-4 hours as needed; patients with prior opiate exposure may require higher initial doses.

120 120 Meperidina DOSING: PEDIATRIC DOSING: PEDIATRIC –Oral, I.M., I.V., SubQ: Children: mg/kg/dose every 3-4 hours as needed; 1-2 mg/kg as a single dose preoperative medication may be used; maximum 100 mg/dose. (Oral route is not recommended for acute pain.) DOSING: ELDERLY DOSING: ELDERLY –Oral: 50 mg every 4 hours –I.M.: 25 mg every 4 hours

121 121 Meperidina DOSING: RENAL IMPAIRMENT –Clcr mL/minute: Administer 75% of normal dose. –Clcr <10 mL/minute: Administer 50% of normal dose. –Repeated use in renal impairment should be avoided due to potential accumulation of neuroexcitatory metabolite. DOSING: HEPATIC IMPAIRMENT Increased narcotic effect in cirrhosis; reduction in dose is more important for oral than I.V. route.

122 122 Meperidina ADVERSE REACTIONS SIGNIFICANT ADVERSE REACTIONS SIGNIFICANT Cardiovascular: Hypotension Central nervous system: Fatigue, drowsiness, dizziness, nervousness, headache, restlessness, malaise, confusion, mental depression, hallucinations, paradoxical CNS stimulation, increased intracranial pressure, seizure (associated with metabolite accumulation), serotonin syndrome Dermatologic: Rash, urticaria Gastrointestinal: Nausea, vomiting, constipation, anorexia, stomach cramps, xerostomia, biliary spasm, paralytic ileus, sphincter of Oddi spasm Genitourinary: Ureteral spasms, decreased urination Local: Pain at injection site Neuromuscular & skeletal: Weakness Respiratory: Dyspnea Miscellaneous: Histamine release, physical and psychological dependence

123 123 Meperidina PRECAUTIONS PRECAUTIONS Meperidine is not recommended for the management of chronic pain. When used for acute pain (in patients without renal or CNS disease), treatment should be limited to 48 hours and doses should not exceed 600 mg/24 hours. Normeperidine (an active metabolite and CNS stimulant) may accumulate and precipitate anxiety, tremors, or seizures; risk increases with renal dysfunction and cumulative dose.

124 124 Meperidina DRUG INTERACTIONS Substrate (minor) of CYP2B6, 2C19, 3A4 Acyclovir: May increase meperidine metabolite concentrations. Use caution. Barbiturates: May decrease analgesic efficacy and increase sedative and/or respiratory depressive effects of meperidine. Cimetidine: May increase meperidine metabolite concentrations; use caution. CNS depressants (including benzodiazepines): May potentiate the sedative and/or respiratory depressive effects of meperidine. MAO inhibitors: May enhance the serotonergic effect of meperidine, which may cause serotonin syndrome. Concurrent use with or within 14 days of an MAO inhibitor is contraindicated. Phenothiazines: May potentiate the sedative and/or respiratory depressive effects of meperidine; may increase the incidence of hypotension. Phenytoin: May decrease the analgesic effects of meperidine Ritonavir: May increase meperidine metabolite concentrations; use caution. Serotonin agonists: Serotonin agonists and meperidine may enhance serotonin levels in the brain. Serotonin syndrome may occur. Serotonin reuptake inhibitors: May potentiate the effects of meperidine, increasing serotonin levels in the brain. Serotonin syndrome may occur. Sibutramine: May enhance the serotonergic effect of meperidine. Serotonin syndrome may occur. Tricyclic antidepressants: May potentiate the sedative and/or respiratory depressive effects of meperidine. In addition, potentially may increase the risk of serotonin syndrome.

125 125 Meperidina PREGNANCY IMPLICATIONS PREGNANCY IMPLICATIONS –Meperidine is known to cross the placenta, which may result in respiratory or CNS depression in the newborn. LACTATION LACTATION –Enters breast milk. contraindicated

126 126 Meperidina REFERENCE RANGE Therapeutic: ng/mL (SI: nmol/L); Toxic: >1000 ng/mL (SI: >4043 nmol/L) TOXICOLOGY / OVERDOSE COMPREHENSIVE Symptoms include CNS depression, respiratory depression, mydriasis, bradycardia, pulmonary edema, chronic tremors, CNS excitability, and seizures. Treatment of overdose includes airway support, establishment of an I.V. line, and administration of naloxone 2 mg I.V. (0.01 mg/kg for children), with repeat administration as necessary, up to a total of 10 mg. Naloxone should not be used to treat meperidine- induced seizures. Naloxone does not reverse the adverse effects of normeperidine.

127 127 Meperidina PHARMACODYNAMICS / KINETICS Onset of action: Analgesic: Oral, SubQ: minutes; I.V.: ~5 minutes Peak effect: SubQ.: ~1 hour; Oral: 2 hours Duration: Oral, SubQ.: 2-4 hours Absorption: I.M.: Erratic and highly variable Distribution: Crosses placenta; enters breast milk Protein binding: 65% to 75% Metabolism: Hepatic; hydrolyzed to meperidinic acid (inactive) or undergoes N-demethylation to normeperidine (active; has 1/2 the analgesic effect and 2-3 times the CNS effects of meperidine) Bioavailability: ~50% to 60%; increased with liver disease Half-life elimination: Parent drug: Terminal phase: Adults: hours, Liver disease: 7-11 hours Normeperidine (active metabolite): hours; can accumulate with high doses or with decreased renal function Excretion: Urine (as metabolites)

128 128 Dosis de carga Dosis de manteni miento FG > 50 ml/min FG ml/min FG < 10 ml/min Dosis suplemta ria tras HD DPCATSCR Meperidina75%50% Clcr mL/minute: Administer 75% of normal dose. Clcr <10 mL/minute: Administer 50% of normal dose. Repeated use in renal impairment should be avoided due to potential accumulation of neuroexcitatory metabolite.

129 Gracias.


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