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TARV. JHÓSEP ANDRÉS BLANCO MEJÍA. Interno Junior Farmacología Clínica. Universidad de La Sabana. CONTENIDO. Presentación de caso clínico. Consideraciones . farmacoterapéuticas. Recomendaciones. ID: 736152

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Slide1

ANTICONVULSIVANTES EN PACIENTE CON VIH EN TARV

JHÓSEP ANDRÉS BLANCO MEJÍA

Interno Junior Farmacología Clínica

Universidad de La Sabana

Slide2

CONTENIDO

Presentación de caso clínico

Consideraciones

farmacoterapéuticas

Recomendaciones

Slide3

EPIDEMIOLOGÍA

Kellinghaus

C,

Engbring

C,

Kovac

S,

Möddel

G,

Boesebeck

F,

Fischera

M,

Anneken

K,

Klönne

K,

Reichelt

D,

Evers

S,

Husstedt

IW.

Frequency

of

seizures

and

epilepsy

in

neurological

HIV-

infected

patients

.

Seizure

. 2008 Jan;17(1):27-33.

Slide4

Kellinghaus

C,

Engbring

C,

Kovac

S,

Möddel

G,

Boesebeck

F,

Fischera

M,

Anneken

K,

Klönne

K,

Reichelt

D,

Evers

S,

Husstedt

IW.

Frequency

of

seizures

and

epilepsy

in

neurological

HIV-

infected

patients

.

Seizure

. 2008 Jan;17(1):27-33.

Slide5

IMPORTANCIA INTERACCIONES

Brew

BJ, Thompson J.

Epilepsy

:

Issues

with

antiepileptic

drug

use in HIV-

infected

patients

.

Nat

Rev

Neurol

. 2012 Mar 13;8(4):187-8.

doi

: 10.1038/nrneurol.2012.36.

Slide6

CONTENIDO

Presentación de caso clínico

Consideraciones

farmacoterapéuticas

Recomendaciones

Slide7

INGRESO

Datos del paciente

Sexo: masculino

Edad: 28 años

Profesión: ayudante de cocina

Fecha de ingreso: 06/03/2018

Motivo de consulta

: Convulsionó en el trabajo

Slide8

ENFERMEDAD ACTUAL

Slide9

REVISIÓN POR SISTEMAS Y ANTECEDENTES

Niega otros síntomas asociados, hábito urinario e intestinal normal

Slide10

EXAMEN FÍSICO

NORMAL

SIGNOS VITALES

TA:

117/84

mmHg

FC:

75

por minuto

FR:

20

por minuto

:

37,1°C

Slide11

IMPRESIÓN DIAGNÓSTICA

Crisis

convulsiva

Epilepsia en tratamiento por historia clínica

Infección por VIH

CD4 400

cel

/ml

y carga viral con 90.000 copias

Síndrome febril en estudio - infección oportunista a

descartar

Slide12

PLAN

Slide13

PARACLÍNICOS

Slide14

RADIOGRAFÍA DE TÓRAX

Slide15

TAC DE CRÁNEO SIMPLE

Slide16

NEUROLOGÍA

Descartar infección como desencadenante.

TAC de cráneo con contraste

De

acuerdo a resultados se definirá indicación de punción

lumbar.

Ajuste de manejo anticonvulsivante:

levetiracetam

500mg cada 8 horas vía oral.

Slide17

TAC CRÁNEO CON CONTRASTE

Slide18

EVOLUCIÓN 07/03/2018

NO nuevos

episodios convulsivos, ni picos

febriles

Examen

físico y Paraclínicos en límites normales.

NO ESTÁ INFECTADO

Salida

con recomendaciones y signos de

alarma

Levetiracetam

1g

cada 12 horas vía oral

Cita

control con neurología

.

Slide19

CONTENIDO

Presentación de caso clínico

Consideraciones

farmacoterapéuticas

Recomendaciones

Slide20

Pau

AK, George JM. Antiretroviral therapy: current drugs. Infect Dis

Clin

North Am. 2014 Sep;28(3):371-402.

Slide21

Cortesía Angélica María

Tellez

M.D

.

Slide22

Abou-Khalil

BW.

Antiepileptic

Drugs

. Continuum (

Minneap

Minn

). 2016 Feb;22(1

Epilepsy

):132-56.

Slide23

Slide24

CYP450

CYP3A4

CYP2C6

Glucoronidación

Unión a proteínas

Bhigjee

AI. Seizures in HIV/AIDS: a southern African perspective.

Acta

Neurol

Scand

Suppl. 2005;181:4-7.

Slide25

Manzardo

C,

Tuset

M, Miró JM,

Gatell

JM. [

Severe

or

life-threatening

interactions

between

antiretrovirals

and non-HIV

drugs

].

Enferm

Infecc

Microbiol

Clin

. 2015 Aug-Sep;33(7):e15-30.

Slide26

Manzardo

C,

Tuset

M, Miró JM,

Gatell

JM. [

Severe

or

life-threatening

interactions

between

antiretrovirals

and non-HIV

drugs

].

Enferm

Infecc

Microbiol

Clin

. 2015 Aug-Sep;33(7):e15-30.

Slide27

INHIBIDORES DE PROTEASA Y ANTICONVULSIVANTES

Los que más interaccionan

Carbamazepina

,

fenitoina

, fenobarbital, oxcarbazepina

En menor medida con

lamotrigina

y ácido

valproico

Existen reportes de falla terapéutica de IP

Brooks

J, Daily J,

Schwamm

L. Protease inhibitors and anticonvulsants. AIDS

Clin

Care. 1997 Nov;9(11):87, 90

.

Lim ML, Min SS,

Eron

JJ,

Bertz

RJ, Robinson M,

Gaedigk

A,

Kashuba

AD.

Coadministration

of

lopinavir

/ritonavir and phenytoin results in two-way drug interaction through cytochrome P-450 induction. J Acquir Immune Defic Syndr

. 2004 Aug 15;36(5):1034-40.

Slide28

LOPINAVIR/RITONAVIR

Lim

ML, Min SS,

Eron

JJ,

Bertz

RJ, Robinson M,

Gaedigk

A,

Kashuba

AD.

Coadministration

of

lopinavir

/

ritonavir

and

phenytoin

results

in

two-way

drug

interaction

through

cytochrome

P-450 induction. J Acquir Immune Defic

Syndr

. 2004

Aug

15;36(5):1034-40.

Slide29

LOPINAVIR/RITONAVIR

Lim

ML, Min SS,

Eron

JJ,

Bertz

RJ, Robinson M,

Gaedigk

A,

Kashuba

AD.

Coadministration

of

lopinavir

/

ritonavir

and

phenytoin

results

in

two-way

drug

interaction

through

cytochrome

P-450 induction. J Acquir Immune Defic

Syndr

. 2004

Aug

15;36(5):1034-40.

Slide30

LOPINAVIR/RITONAVIR

Lim

ML, Min SS,

Eron

JJ,

Bertz

RJ, Robinson M,

Gaedigk

A,

Kashuba

AD.

Coadministration

of

lopinavir

/

ritonavir

and

phenytoin

results

in

two-way

drug

interaction

through

cytochrome

P-450 induction. J Acquir Immune Defic

Syndr

. 2004

Aug

15;36(5):1034-40.

Slide31

LOPINAVIR/RITONAVIR

Lim

ML, Min SS,

Eron

JJ,

Bertz

RJ, Robinson M,

Gaedigk

A,

Kashuba

AD.

Coadministration

of

lopinavir

/

ritonavir

and

phenytoin

results

in

two-way

drug

interaction

through

cytochrome

P-450 induction. J Acquir Immune Defic

Syndr

. 2004

Aug

15;36(5):1034-40.

Slide32

EFAVIRENZ

Okulicz

JF,

Grandits

GA, French JA,

Perucca

E, George JM,

Landrum

ML, Acosta EP,

Birbeck

GL.

The

impact

of

enzyme-inducing

antiepileptic

drugs

on

antiretroviral

drug

levels

: a case-control

study

.

Epilepsy Res. 2013 Feb;103(2-3):245-53

Slide33

NEVIRAPINA

Okulicz

JF,

Grandits

GA, French JA,

Perucca

E, George JM,

Landrum

ML, Acosta EP,

Birbeck

GL.

The

impact

of

enzyme-inducing

antiepileptic

drugs

on

antiretroviral

drug

levels

: a case-control

study

.

Epilepsy Res. 2013 Feb;103(2-3):245-53

Slide34

LOPINAVIR

Okulicz

JF,

Grandits

GA, French JA,

Perucca

E, George JM,

Landrum

ML, Acosta EP,

Birbeck

GL.

The

impact

of

enzyme-inducing

antiepileptic

drugs

on

antiretroviral

drug

levels

: a case-control

study

.

Epilepsy Res. 2013 Feb;103(2-3):245-53

Slide35

NEVIRAPINA VS NEVIRAPINA + FENITOINA

Fillekes

Q, Muro EP,

Chunda

C,

Aitken

S,

Kisanga

ER,

Kankasa

C,

Thomason

MJ,

Gibb

DM, Walker AS, Burger DM.

Effect

of 7

days

of

phenytoin

on

the

pharmacokinetics

of and

the

development of resistance to

single-

dose

nevirapine

for

perinatal HIV

prevention

: a

randomized

pilot

trial. J

Antimicrob

Chemother

. 2013 Nov;68(11):2609-15.

Slide36

Fillekes

Q, Muro EP,

Chunda

C,

Aitken

S,

Kisanga

ER,

Kankasa

C,

Thomason

MJ,

Gibb

DM, Walker AS, Burger DM.

Effect

of 7

days

of

phenytoin

on

the

pharmacokinetics

of and

the

development

of resistance to

single-

dose

nevirapine

for

perinatal HIV

prevention

: a

randomized

pilot

trial. J

Antimicrob

Chemother

. 2013 Nov;68(11):2609-15.

Slide37

LOPINAVIR Y LAMOTRIGINA

van

der Lee MJ,

Dawood

L, ter

Hofstede

HJ, de

Graaff-Teulen

MJ, van

Ewijk-Beneken

Kolmer

EW,

Caliskan-Yassen

N,

Koopmans

PP, Burger DM.

Lopinavir

/

ritonavir

reduces

lamotrigine

plasma

concentrations

in

healthy

subjects

.

Clin

Pharmacol Ther. 2006 Aug;80(2):159-68.

Slide38

LOPINAVIR Y LAMOTRIGINA

van

der Lee MJ,

Dawood

L, ter

Hofstede

HJ, de

Graaff-Teulen

MJ, van

Ewijk-Beneken

Kolmer

EW,

Caliskan-Yassen

N,

Koopmans

PP, Burger DM.

Lopinavir

/

ritonavir

reduces

lamotrigine

plasma

concentrations

in

healthy

subjects

.

Clin

Pharmacol Ther. 2006 Aug;80(2):159-68.

Slide39

LOPINAVIR Y LAMOTRIGINA

van

der Lee MJ,

Dawood

L, ter

Hofstede

HJ, de

Graaff-Teulen

MJ, van

Ewijk-Beneken

Kolmer

EW,

Caliskan-Yassen

N,

Koopmans

PP, Burger DM.

Lopinavir

/

ritonavir

reduces

lamotrigine

plasma

concentrations

in

healthy

subjects

.

Clin

Pharmacol Ther. 2006 Aug;80(2):159-68.

Slide40

ZIDOVUDINA Y ÁCIDO VALPROICO

Estudios In vitro muestran una alta inhibición de UGT por ácido

valproico

.

Microsomas

hepáticos humanos y mediciones por cromatografía

Concentraciones de inhibición del 50% de UGT

Slide41

ZIDOVUDINA Y ÁCIDO VALPROICO

Trapnell

CB,

Klecker

RW,

Jamis

-Dow C, Collins JM.

Glucuronidation

of 3'-azido-3'-deoxythymidine (

zidovudine

)

by

human

liver

microsomes

:

relevance

to

clinical

pharmacokinetic

interactions

with

atovaquone, fluconazole, methadone

, and

valproic

acid

.

Antimicrob

Agents

Chemother

. 1998 Jul;42(7):1592-6.

Slide42

DOLUTEGRAVIR Y CARBAMAZEPINA

Disminuye AUC y concentraciones plasmáticas

AUC 49%,

Cmax

33%,

Cmin 73

%

Si se dan juntos

dolutegravir

a

50 mg/12

h.

Ribera

E,

Podzamczer

D. [

Mechanisms

of

action

,

pharmacology

and

interactions

of

dolutegravir

].

Enferm

Infecc

Microbiol Clin. 2015 Mar;33 Suppl 1:2-8.

Slide43

RESUMEN DE REPORTES

Trapnell

CB,

Klecker

RW,

Jamis

-Dow C, Collins JM.

Glucuronidation

of 3'-azido-3'-deoxythymidine (

zidovudine

)

by

human

liver

microsomes

:

relevance

to

clinical

pharmacokinetic

interactions

with

atovaquone, fluconazole, methadone

, and

valproic

acid

.

Antimicrob

Agents

Chemother

. 1998 Jul;42(7):1592-6.

Slide44

ESTEATOSIS HEPÁTICA

Amacher

DE,

Chalasani

N.

Drug-induced

hepatic

steatosis

.

Semin

Liver

Dis

. 2014 May;34(2):205-14.

Slide45

RAMS MOLESTAS

145

adultos

de Zambia

Cuestionario de síntomas antes y después de la intervención

TARV con anticonvulsivantes (n=20) Vs

sólo

TARV (n=43) VS no

teraPia

(n=80)

En el grupo combinado se reportó más dolor de cabeza, fatiga generalizada, concentración,

depresión

con respecto al grupo no tratado (p<0.01)

Con respecto a la primera

medición,

grupo combinado tenía más náusea y

vómito

(P<0.05)

Las RAMS no afectaron adherencia 95% Vs 98% entre los que recibieron algún tratamiento

Adherencia

a 6 meses fue igual por falta de medicamentos (56%)

Elafros

MA,

Birbeck

GL,

Gardiner

JC,

Siddiqi

OK, Sikazwe I, Paneth N, Bositis CM, Okulicz JF. Patient-Reported Adverse

Effects

Associated

with

Combination

Antiretroviral

Therapy

and

Coadministered

Enzyme-Inducing

Antiepileptic

Drugs

. Am J

Trop

Med

Hyg

.

2018

Jun;96(6):1505-1511.

Slide46

GUÍAS AAN E ILAE 2012

COMBINACIÓN

RECOMENDACIÓN

GRADO

RECOMENDACIÓN

Fenitoina

y

lopinavir

/

ritonavir

aumentar TARV 50%

Grado C

Ácido

valproico

y

zidovudina

reducir dosis de TARV

Ácido

valproico

y

efavirenz

Raltegravir

o

atazanavir

en monoterapia y

lamotrigina

Raltegravir

y

midazolam

Ritonavir

/

atazanavir

y

lamotrigina

incremento 50%

lamotrigina

Evitar

combinar IP o

NNRTI's

con anticonvulsivantes inductores de enzimas como

fenitoina

,

carbamazepina

,

oxcarbazepina

y fenobarbital

. (Grado C)

Birbeck

GL, French JA,

Perucca

E, Simpson DM,

Fraimow

H, George JM,

Okulicz

JF, Clifford DB,

Hachad

H, Levy RH; Quality Standards Subcommittee of the American Academy of Neurology; Ad Hoc Task Force of the Commission on Therapeutic Strategies of the International League Against Epilepsy. Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Ad Hoc Task Force of the Commission on Therapeutic Strategies of the International League Against Epilepsy. Neurology. 2012 Jan 10;78(2):139-45.

Slide47

GESTIÓN DEL RIESGO

Hugen

PW, Burger DM,

Brinkman

K, ter

Hofstede

HJ,

Schuurman

R,

Koopmans

PP,

Hekster

YA.

Carbamazepine

--

indinavir

interaction

causes antiretroviral

therapy

failure

. Ann

Pharmacother

. 2000 Apr;34(4):465-70.

Arazo

Garcés P, de los Santos Gil I. [

Pharmacokinetic

interactions

]. Enferm Infecc Microbiol Clin. 2013 Jun;31

Suppl

2:12-9

.

Jiménez-

Nácher

I, Alvarez E,

Morello

J, Rodriguez-

Nóvoa

S, de Andrés S, Soriano V. Approaches for understanding and predicting drug interactions in human immunodeficiency virus-infected patients. Expert

Opin

Drug

Metab

Toxicol

. 2011 Apr;7(4):457-77.

doi

: 10.1517/17425255.2011.558839.

Epub

2011 Feb 23.

INTERACCIÓN

MECANISMO

GESTIÓN

Carbamazepina

/

oxcarbazepina

/

fenitoina

/fenobarbital - Inhibidores de proteasa

*

Dolutegravir

y

carbamazepina

Anticonvulsivantes inducen y los IP inhibe CYP3A4. Considerar substituir anticonvulsivante

Monitorizar eficacia de IP y toxicidad de anticonvulsivante.

Subir

dosis de IP 50%

Cambiar anticonvulsivante

Ácido

valproico

/

lamotrigina

-

ritonavir

Ritonavir

induce

glucoronil

transferasa

Monitorizar eficacia de anticonvulsivantes.

Subir dosis de anticonvulsivante.

Felbamato

/BZD/

Etosuxamida

– inhibidores de proteasa

Inhibición CYP 2C y 3A

Monitorizar toxicidad de anticonvulsivantes y eficacia de IP

Subir

dosis de IP 50%

Cambiar anticonvulsivante

Slide48

CONCLUSIONES

Slide49

BIBLIOGRAFÍA

Arazo

Garcés P, de los Santos Gil I. [

Pharmacokinetic

interactions

].

Enferm

Infecc

Microbiol

Clin

. 2013 Jun;31

Suppl

2:12-9.

Bhigjee

AI. Seizures in HIV/AIDS: a southern African perspective.

Acta

Neurol

Scand

Suppl. 2005;181:4-7.

van

Luin

M,

Colbers A, Verwey

-van Wissen CP, van Ewijk-Beneken-Kolmer EW, van der Kolk M, Hoitsma

A, da Silva HG, Burger DM. The effect of raltegravir on the glucuronidation of lamotrigine. J Clin Pharmacol. 2009 Oct;49(10):1220-7.Hugen PW, Burger DM, Brinkman K, ter Hofstede HJ, Schuurman R, Koopmans PP, Hekster YA. Carbamazepine--

indinavir

interaction causes antiretroviral therapy failure. Ann

Pharmacother

. 2000 Apr;34(4):465-70.

Brew BJ, Thompson J. Epilepsy: Issues with antiepileptic drug use in HIV-infected patients.

Nat

Rev

Neurol

. 2012 Mar 13;8(4):187-8.

doi

: 10.1038/nrneurol.2012.36.

Kellinghaus

C,

Engbring

C,

Kovac

S,

Möddel

G,

Boesebeck

F,

Fischera

M,

Anneken

K,

Klönne

K,

Reichelt

D, Evers S,

Husstedt

IW. Frequency of seizures and epilepsy in neurological HIV-infected patients. Seizure. 2008 Jan;17(1):27-33.

Okulicz

JF,

Grandits

GA, French JA,

Perucca

E, George JM, Landrum ML, Acosta EP,

Birbeck

GL. The impact of enzyme-inducing antiepileptic drugs on antiretroviral drug levels: a case-control study. Epilepsy Res. 2013 Feb;103(2-3):245-53

AAN. Appendix D. Summary of Evidence-based Guideline for CLINICIANS: ANTIEPILEPTIC DRUG SELECTION FOR PEOPLE WITH HIV/AIDS. Continuum (

Minneap

Minn

). 2016 Feb;22(1 Epilepsy):287-8.

doi

: 10.1212/01.CON.0000480842.81389.be.

Honda M,

Yasuoka

A, Aoki M, Oka S. A generalized seizure following initiation of

nelfinavir

in a patient with human immunodeficiency virus type 1 infection, suspected due to interaction between

nelfinavir

and phenytoin. Intern Med. 1999 Mar;38(3):302-3.

Amacher

DE,

Chalasani

N. Drug-induced hepatic

steatosis

.

Semin

Liver Dis. 2014 May;34(2):205-14.

Devarbhavi

H, Andrade RJ. Drug-induced liver injury due to antimicrobials, central nervous system agents, and

nonsteroidal

anti-inflammatory drugs.

Semin

Liver Dis. 2014 May;34(2):145-61.

Ji

P,

Damle

B,

Xie

J, Unger SE,

Grasela

DM,

Kaul

S. Pharmacokinetic interaction between

efavirenz

and carbamazepine after multiple-dose administration in healthy subjects. J

Clin

Pharmacol

. 2008 Aug;48(8):948-56.

Fillekes

Q,

Muro

EP,

Chunda

C, Aitken S,

Kisanga

ER,

Kankasa

C, Thomason MJ, Gibb DM, Walker AS, Burger DM. Effect of 7 days of phenytoin on the pharmacokinetics of and the development of resistance to single-dose

nevirapine

for perinatal HIV prevention: a randomized pilot trial. J

Antimicrob

Chemother

. 2013 Nov;68(11):2609-15.

Jiménez-

Nácher

I, Alvarez E,

Morello

J, Rodriguez-

Nóvoa

S, de Andrés S, Soriano V. Approaches for understanding and predicting drug interactions in human immunodeficiency virus-infected patients. Expert

Opin

Drug

Metab

Toxicol

. 2011 Apr;7(4):457-77.

doi

: 10.1517/17425255.2011.558839.

Epub

2011 Feb 23.

Brooks J, Daily J,

Schwamm

L. Protease inhibitors and anticonvulsants. AIDS

Clin

Care. 1997 Nov;9(11):87, 90.

Ribera E,

Podzamczer

D. [Mechanisms of action, pharmacology and interactions of

dolutegravir

].

Enferm

Infecc

Microbiol

Clin

. 2015 Mar;33

Suppl

1:2-8.

Manzardo

C,

Tuset

M,

Miró

JM,

Gatell

JM. [Severe or life-threatening interactions between

antiretrovirals

and non-HIV drugs].

Enferm

Infecc

Microbiol

Clin

. 2015 Aug-Sep;33(7):e15-30.

 

Lim ML, Min SS,

Eron

JJ,

Bertz

RJ, Robinson M,

Gaedigk

A,

Kashuba

AD.

Coadministration

of

lopinavir

/ritonavir and phenytoin results in two-way drug interaction through cytochrome P-450 induction. J

Acquir

Immune

Defic

Syndr

. 2004 Aug 15;36(5):1034-40.

Bates DE, Herman RJ. Carbamazepine toxicity induced by

lopinavir

/ritonavir and

nelfinavir

. Ann

Pharmacother

. 2006 Jun;40(6):1190-5.

Brodie MJ,

Mintzer

S, Pack AM,

Gidal

BE,

Vecht

CJ, Schmidt D. Enzyme induction with antiepileptic drugs: cause for concern?

Epilepsia

. 2013 Jan;54(1):11-27.

van der Lee MJ,

Dawood

L,

ter

Hofstede

HJ, de

Graaff-Teulen

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