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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Presentations text content in ANTICONVULSIVANTES EN PACIENTE CON VIH EN
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
T°
:
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.
Slide23Slide24
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
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.
Robertson SM,
Penzak
SR, Lane J, Pau AK,
Mican
JM. A potentially significant interaction between
efavirenz
and phenytoin: a case report and review of the literature.
Clin
Infect Dis. 2005 Jul 15;41(2):e15-8.
Epub
2005 Jun 7.
Romanelli
F, Jennings HR,
Nath
A, Ryan M, Berger J. Therapeutic dilemma: the use of anticonvulsants in HIV-positive individuals. Neurology. 2000 Apr 11;54(7):1404-7.
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.
Liedtke
MD, Lockhart SM,
Rathbun
RC. Anticonvulsant and antiretroviral interactions. Ann
Pharmacother
. 2004 Mar;38(3):482-9.
Epub
2004 Jan 23.
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
. 2017 Jun;96(6):1505-1511.
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.
Pau AK, George JM. Antiretroviral therapy: current drugs. Infect Dis
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Presentations text content in ANTICONVULSIVANTES EN PACIENTE CON VIH EN
ANTICONVULSIVANTES EN PACIENTE CON VIH EN TARV
JHÓSEP ANDRÉS BLANCO MEJÍA
Interno Junior Farmacología Clínica
Universidad de La Sabana
Slide2CONTENIDO
Presentación de caso clínico
Consideraciones
farmacoterapéuticas
Recomendaciones
Slide3EPIDEMIOLOGÍA
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.
Slide4Kellinghaus
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.
Slide5IMPORTANCIA 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.
Slide6CONTENIDO
Presentación de caso clínico
Consideraciones
farmacoterapéuticas
Recomendaciones
Slide7INGRESO
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
Slide8ENFERMEDAD ACTUAL
Slide9REVISIÓN POR SISTEMAS Y ANTECEDENTES
Niega otros síntomas asociados, hábito urinario e intestinal normal
Slide10EXAMEN FÍSICO
NORMAL
SIGNOS VITALES
TA:
117/84
mmHg
FC:
75
por minuto
FR:
20
por minuto
T°
:
37,1°C
Slide11IMPRESIÓN 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
Slide12PLAN
Slide13PARACLÍNICOS
Slide14RADIOGRAFÍA DE TÓRAX
Slide15TAC DE CRÁNEO SIMPLE
Slide16NEUROLOGÍA
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.
Slide17TAC CRÁNEO CON CONTRASTE
Slide18EVOLUCIÓN 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
.
Slide19CONTENIDO
Presentación de caso clínico
Consideraciones
farmacoterapéuticas
Recomendaciones
Slide20Pau
AK, George JM. Antiretroviral therapy: current drugs. Infect Dis
Clin
North Am. 2014 Sep;28(3):371-402.
Slide21Cortesía Angélica María
Tellez
M.D
.
Slide22Abou-Khalil
BW.
Antiepileptic
Drugs
. Continuum (
Minneap
Minn
). 2016 Feb;22(1
Epilepsy
):132-56.
Slide23Slide24CYP450
CYP3A4
CYP2C6
Glucoronidación
Unión a proteínas
Bhigjee
AI. Seizures in HIV/AIDS: a southern African perspective.
Acta
Neurol
Scand
Suppl. 2005;181:4-7.
Slide25Manzardo
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.
Slide26Manzardo
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.
Slide27INHIBIDORES 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.
Slide28LOPINAVIR/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.
Slide29LOPINAVIR/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.
Slide30LOPINAVIR/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.
Slide31LOPINAVIR/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.
Slide32EFAVIRENZ
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
Slide33NEVIRAPINA
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
Slide34LOPINAVIR
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
Slide35NEVIRAPINA 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.
Slide36Fillekes
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.
Slide37LOPINAVIR 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.
Slide38LOPINAVIR 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.
Slide39LOPINAVIR 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.
Slide40ZIDOVUDINA 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
Slide41ZIDOVUDINA 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.
Slide42DOLUTEGRAVIR 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.
Slide43RESUMEN 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.
Slide44ESTEATOSIS HEPÁTICA
Amacher
DE,
Chalasani
N.
Drug-induced
hepatic
steatosis
.
Semin
Liver
Dis
. 2014 May;34(2):205-14.
Slide45RAMS 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.
Slide46GUÍAS 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.
Slide47GESTIÓN 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
Slide48CONCLUSIONES
Slide49BIBLIOGRAFÍA
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
].
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