Pharmacogenetics, antiamebic, antifungal drugs Flashcards Preview

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Flashcards in Pharmacogenetics, antiamebic, antifungal drugs Deck (14):

N-acetyltransferase-2 (Isoniazid)

-Isoniazid inactivated by N-acetylation
-Both slow and fast acetylators (autosomal recessive autosomal dominant, respectively)
-50% or population is slow phenotype (same exact nz, but less of it)
-Elevation of plasma isoniazid increases excretion of vit. B6 and leads to artificial B6 deficiency and neuropathy
-B6 supplementation prevents neuropathy


Thiopurine S-methyl-transferase (TMPT)

-6-mercaptopurine (and 6-thioguanine and azathioprine, which are both converted into 6-mercaptopurine) is inactivated by TMPT
-Low, intermediate, and high phenotypes (high is by far most common). Autosomal dominant
-Measured by erythrocyte TMPT activity (except in blood transfusions, when the genotype is measured)
-Low TMPT leads to elevated levels of thiopurines and more bone marrow destruction (must decrease dose)


Alcohol dehydrogenase (ADH)

-Atypical B2 subunit (85% of east asians) leads to rapid metabolization of EtOH to AcALD
-Outcome depends on ALDH2 expression


Aldehyde dehydrogenase (ALDH)

-ALDH2 variant is an inactive nz (single base change) that occurs in 50% of east asians (autosomal dominant)
-Cannot oxidize acetylaldehyde, leads to flushing and disulfiram-like effects
-Alcoholism rare in these individuals


CYP2D6 (P450 isonz)

-Converts tamoxifen into endoxifen (100x the affinity for estrogen receptor)
-Can be "poor metabolizer" phenotype or "extensive metabolizer"(autosomal recessive)
-Identify via molecular methods
-Poor metabolizers mostly caucasians (7%) and blacks/asians (3%)
-Tamoxifen not converted to most active form, leads to increased risk of recurrence of breast cancer


CYP2C9*3 (P450 isonz)

-*3 variant does not inactivate warfarin (in <1% of population)
-Warfarin dose decreased to 10-25%


Warfarin receptor

-Resistance to warfarin-induced anticoagulation (autosomal dominant)
-Rare frequency, due to mutation in receptor leading to lower warfarin affinity (vitamin K epoxide reductase)
-Dose is increased 10-30x



-Effective in killing amebae in bowel wall, liver, and tissues (not for intestinal lumen)
-Nitro group of drug reduced by ferridoxin in the amebae, product react w/ DNA and proteins
-It is readily absorbed after oral administration
-Metabolized by CYP (drug interaction)
-Adverse effects: metallic taste, dry mount, disulfiram-like effects (blocks ALDH: vomiting, fever, chills, chest pain), pancreatitis and peripheral neuropathy are rare
-Contraindicated in pregnant or nursing women/children (cat. C)


Luminal amebicides

-Diloxanide Furoate, Iodoquinol, paromomycin
-Diloxanide: only 10% becomes active (90% conjugated, absorbed, and excreted) and the mechanism is not known. No serious side effects. Has cysticidal activity. Contraindicated for children <2 and pregnant women
-Iodoquinol: 90% not absorbed and active (10% absorbed and excreted), mechanism is not known. High doses produces optic nerve atrophy, interferes w/ thyroid test. Has cysticidal activity
-Paromomycin: aminoglycoside (inhibits 30S ribosome), is not absorbed by the GI tract (no systemic toxicity, ok for pregnant women). P for pregnant


Treatment of intestinal amebiasis

-Asymptomatic infection: iodoquinol or paromomycin (diloxanide furoate as alternative)
-Mild-moderate: iodoquinol, or paromomycin, or diloxanide AND metronidazole (oral)
-Severe (dysentery): Same as above but IV metronidazole
-Hepatic abscess: same as above plus choloquine


Amphotericin B

-Antifungal: binds to ergosterole and makes pores in fungal membrane (IV only, does not enter CSF)
-Adverse effects: infusion-related toxicity (amphoterrible: fever, chills), renal toxicity (most significant toxic run, minimize by IVNS prior to and using liposomal preparation
-Broad spectrum for life-threatening infections
-Only systemic drug for pregnant women (cat. B)



-Antifungal: enters fungus cell through permease on cell membrane
-In fungus it is converted to fluorouracil which inhibits thymidylate synthase and RNA synthesis
-low protein binding and does enter CSF
-Adverse effects: causes bone marrow depression (not used in AIDS patients or chemo patients)
-Uses restricted to cryptococcus and candida sp.
-Not used as a single agent (resistance easily developed)
-Used in combination w/ amphotericin B


Systemic azoles

-They block the synthesis of ergosterol by inhibiting the fungal P450 (fungistatic)
-Ketoconazole and itraconazole: given orally, antacids decrease absorption, do not enter CSF (protein bound)
-Ketoconazole is less selective for fungal P450, leading to inhibition of gonadal steroid hormone synthesis (impotence/infertility). Used for mucocutaneous candidiasis and nonmeningeal coccidiodomyosis
-Itraconazole: broad spectrum antifungal
-Fluconazole: can be give orally or IV, does enter CSF (not protein bound), high therapeutic index
-Fluconazole used for meningeal, UTI, prohylaxis


Synergistic interactions

-Amphotericin B + flucytosine: amphotericin makes pores, flucytosine enters them (overcomes resistance), flu cytosine enters CSF and amphotericin cannot
-Considerations: low dose of amphotericin or renal failure occurs (then lower flucytosine)
-Amphotericin B and azoles: antagonistic interaction since azoles block the synthesis of ergasterol and amphotericin needs it to work
-Azoles w/ other drugs: Azoles inhibit P450 and decrease drug metabolism (decrease dose of other drugs or do not combine)
-Rifampin/isoniazid (P450 inducers): increase metabolism of azoles, thus must increase the dose