Interaksi obat-obatan HIV dan infeksi oportunistik

Mekanisme interaksi obat

1. farmakokinetik : mengubah absorpsi, transport, distribusi, metabolism, ekskresi obat.

2. farmakodinamik: mengubah respon farmakologis. Respon bisa aditif, sinergis atau antagonis.

Interaksi metabolism

-Semua obat HIV protease inhibitor dan non nucleoside reverse transcriptase inhibitor di
metaolisme oleh CYP3A4

-ritonavir, nelfinavir, and efavirenz dapat menjadi substrat, induser, inhibitor tergantung
kombinasinya

-ritonavir sebagai inhibitor CYP3A4 +saquinavirkadar saquinavir meningkat

-nevirapin sbg induser + indinavir atau amprenavirpenurunan AUC

Intestinal Metabolism and P-Glycoprotein

-grapefruit sbg inhibitor CYP3A4 di metabolism ususAUC saquinavir meningkatkan 50-150

%

-ritonavir sbg inhibitor poten P-glycoprotein (tugas: meningkatkan efluks obat dari sel)
meningkatkan kecepatan abs obat

-rifampin menginduksi p glycoprotein + digoxinpenurunan kadar digoxin

-ketoconazole inhibitor CYP3A4 dan P glycolpeningkatan kadar saquinavir dan ritonavir di

cerebrospinal fluid

Absorpsi obat

-fluoroquinolon denga kation divalent dan trivalent  menurunkan AUC quinolone >90%

-formulasi didanosine (mengandung al-mg/buffer antasida)+ciprofloxacinpenurunan AUC

cipro 80%, interaksi dapt dihindari dengan jeda 2 jam fluoroquinolone duluan, atau 6 jam setelah
antasida atau dengan formulasi enteric coated didanosin

-pengaruh pada ph gastric

- ketoconazol+h2ra, antasida atau ppipenurunan abs keto(keto diabs di ph rendah)

- itraconazole (abs di ph rendah)dikonsumsi dengan makanan
- fluconazoletdk terpengaruh ph
eliminasi renal

-probenesid dan trimethoprimkompetitif inhibitor pada sekresi tubular renal

-probenesid+acyclovirpeningkatan acy

-tmp-sulfametoksazol+lamivudin penigkatan lamivudin

-probenesid+zidovudinpeningkatan zidovudin (krn pro hambat hepatic glucuronidasi)

NUCLEOSIDE-ANALOGUE REVERSETRANSCRIPTASE INHIBITORS

-Because nucleoside-analogue reverse-transcriptase

inhibitors are primarily eliminated by the kidneys, they
do not interact with other drugs through the cytochrome
P-450 system. These drugs can be given with
protease inhibitors and non-nucleoside reverse-transcriptase
inhibitors without dosage adjustments.

-Nucleoside reverse-transcriptase inhibitors are prodrugs

that require intracellular phosphorylation to the
active moiety, ex Ribavirin decreases the phosphorylation of
zidovudine and stavudine in vitro, resulting in decreased
concentrations of the active compound.

-Ribavirin decreases the phosphorylation of

zidovudine and stavudine in vitro, resulting in decreased
concentrations of the active compound.

-Hydroxyurea, an inhibitor of the enzyme ribonucleotide

reductase, which is involved in the formation of
deoxynucleotides, increases the antiviral action of didanosine.

NON-NUCLEOSIDE REVERSETRANSCRIPTASEINHIBITORS

-Nevirapine and efavirenz are

moderate inducers of CYP3A4

-nevirapin+indinavir atau saquinavir menurunkan kadar indi saqui tapi tdk rito dan nelvi (krn
tidak di metabolism ektensif CYP3A4 dan mereka dpt autoinduksi)

-Efavirenz inhibition of the CYP2C9 or CYP2C19rito dan nelvi kadar meningkat

-nev I dan eva  menurunkan kaadar methadonemethadone withdrawal
-delavirdine (inhibitor poten cyp) hati2 pada obat natiaritmia, ccb, sedative hipnotik,
quinidine, vasokonstriksi (ergotamineiskemik perifer), antikanker (etoposide, paclitaxel
peningkatan toksisitas)

HIV PROTEASE INHIBITOR

-HIV-protease inhibitors merupakan inhibitors of
CYP3A4 enzymes and are contraindicated in combination
with certain antiarrhythmic drugs, sedative and
hypnotic drugs, ergot derivatives, cisapride, and the
3-hydroxy-3-methylglutaryl coenzyme A reductase
inhibitors lovastatin and simvastatin
-ritonavirpoten inhibitor>indi, amprenavir, nelfinavir>saquinavir
-ritonavirinduksi diri sendiri 14 hari pertama, induksi CYP1A2 (menurunkan teofilin),
meningkatkan aktivitas glukorosiltransferase (penurunan estradiol)
-Other potent enzyme inducers, such as phenytoin,
phenobarbital, and carbamazepine, can cause similar
reductions in plasma concentrations of protease inhibitors.
-protease inhibitor+azitromisin peningkatan auc klaritromisin

DRUGS FOR OPPORTUNISTIC INFECTIONS

-Ketoconazole and
itraconazole, which are potent inhibitors of CYP3A4
and moderate inhibitors of P-glycoprotein, can be
given to increase plasma concentrations of protease
inhibitors

alternative

-st john wortinduksi CYP DAN P-glycoproteinmenurunkan protease inhibitors and non-
nucleoside reverse-transcriptase inhibitorsresistensi
-Raw garlic and garlic supplements inhibit the activity of CYP3A4+ritonavirgastrointestinal
toxicity

Drug–Cytokine Interactions
-interleukin-6 and TNF-a inhibited
cytochrome P-450
-interleukin-2meningkatkan sitokinthe area under the curve for plasma indinavir
was increased

ROLE OF THERAPEUTIC DRUG MONITORING

determination of plasma drug concentrations
may have a role in the evaluation of drug
interactions, provided that the limitations in the use
of plasma drug measurements to evaluate individual
patients are recognized. These limitations include
the large variability in pharmacokinetic characteristics
within individual patients, lack of information on specific
therapeutic ranges and target concentrations (i.e.,
data on the concentrations that cause 50 percent inhibition),
variations in drug binding to a1-acid glycoprotein
and albumin, slow viral responses to changes
in plasma drug concentrations, and clinical interpretations
of measurements.