Pharmacogenetics, antiamebic, antifungal drugs

Question 1

N-acetyltransferase-2 (Isoniazid)

Answer 1

• 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

Question 2

Thiopurine S-methyl-transferase (TMPT)

Answer 2

• 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)

Question 3

Alcohol dehydrogenase (ADH)

Answer 3

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

Question 4

Aldehyde dehydrogenase (ALDH)

Answer 4

• 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

Question 5

CYP2D6 (P450 isonz)

Answer 5

• 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

Question 6

CYP2C9*3 (P450 isonz)

Answer 6

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

Question 7

Warfarin receptor

Answer 7

• 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

Question 8

Metronidazole

Answer 8

• 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)

Question 9

Luminal amebicides

Answer 9

• 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

Question 10

Treatment of intestinal amebiasis

Answer 10

• 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

Question 11

Amphotericin B

Answer 11

• 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)

Question 12

Flucytosine

Answer 12

• 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

Question 13

Systemic azoles

Answer 13

• 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

Question 14

Synergistic interactions

Answer 14

• 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