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Antifungal Drugs
The big picture:
DRUG INFECTION ROUTE MECHANISM CLASS
Amphotericin B
(deoxycholate)
Deep IV Ergosterol binding
Amphotericin B Polyene
(lipid formulation)
Nystatin Derm/yeast PO/topical/vaginal
Ketoconazole Deep/derm PO/topical
Fluconazole
Deep IV/PO
Itraconazole Ergosterol synthesis Azole
Clotrimazole
Derm/yeast Topical/vaginal
Miconazole
Flucytosine Deep PO DNA/protein synthesis Pyrimidine
Caspofungin
Micafungin Deep IV Cell wall synthesis Echinocandin
Anidulafungin
Gresofulvin Derm PO Microtubule formation Griseofulvin
Terbinafine Derm PO/topical Squalene synthesis Allylamine
General principles: need to be highly specific for fungal target without affecting human counterparts (tough because
both are eukaryotes)
Sterol biosynthesis:
First part (common to both animals & fungi)
1. Squalene 2,3-oxidosqualene (via squalene 2,3-epoxidase)
2. lanosterol (via 14-α-demethylase)
3. zymosterol
Second part
1. Humans: zymosterol cholesterol
2. Fungi: zymosterol ergosterol
Key point: fungi use ergosterol (more hydrophobic & rigid) instead of cholesterol in their cell membranes
Effects: forms cylindrical channel (hydrophobic sides outside, against cell membrane) when bound to sterols &
allows leakage of small molecules resulting in fungal death
Selective Toxicity: Binds more avidly to ergosterol (fungi) than cholesterol; selective toxicity not great
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Target: ergosterol biosynthesis
Note: none of our current drugs target the fungi-specific part of ergosterol biosynthesis!
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Target: microtubule formation
Griseofulvin Mechanism of Action: Antifungal agent; Interferes with microtubule formation
Effects: actively transported into fungal cells; disrupts microtubules (mitotic & cytoplasmic), cell cycle arrest at
mitosis, formation of multinucleate cells.
Selective Toxicity: Humans don't actively transport into our cells
Indications: Severe infection of hair, nails, palm, soles (concentrates highly in keratin layers)
Administration: Almost complete distribution; goes to keratin layers
Toxicity: Relatively safe (GI distress, temporary headache)
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Chemotherapy of Parasitic Infections
1/3 of world’s pop has parasites. 1:5 Americans! NO VACCINES so you have to use drugs for prophylaxis & treatment
Can classify as protozoa or helminths, or (more useful for pharm): Gastrointestinal vs Tissue/blood
1. Parasite motility
pyrantel Mechanism of Action: Antihelminthic agent. Ach analog; neuromuscular blocking agent & Ach inhibitor
(causes spastic paralysis & constant muscle contraction of worm)
Effects:Worms can't resist bowel peristalsis; get swept out
Selective Toxicity: Luminal agent (poorly absorbed) - only affects parasites
praziquantel Mechanism of Action: Antihelminthic agent. Causes tetanic contraction of schistotomes (alters Ca
transport) & alters membrane integrity
Effects: Worms can't resist bowel peristalsis; get swept out to liver/lungs (portal circulation from gut or
systemic from bladder area). Surface of worm disrupted then, leading to death.
Selective Toxicity: unknown (NOT LUMINAL)
Enteric helminths live in anaerobic environment, so they have a special, different way to get energy:
Transport glucose across membrane; different end of glycolysis (malate) & Krebs-cycle type thing
Uses succinate dehydrogenase in respiratory chain (reverse direction from humans: fumaratesuccinate)
Both the transporter & the succinate DH enzyme are different isoforms in parasites
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Benzimidazoles:
albendazole Mechanism of Action: Antihelminthic agent.
Block glucose transport
mebendazole inhibit succinate dehydrogenase activity; an enzyme used in parasite's respiratory chain.
(also disrupt microtubules selectively)
Effects: No energy for parasites; die & get swept out
Selective Toxicity: Helminths have different metabolism because they're anaerobic; parasitic isoforms are
different for these enzymes than humans'.
Albendazole: Variable absorption (good to get more coverage; bad because of human
interactions - not a luminal agent)
Mebendazole: Luminal agent (good absorption
Indications:
Both: Gut organisms (enterobius, ascaris, trichuris, hookworm)
Albendazole: tissue too (strongyloides, tapeworm which have tissue parts of life cycle)
Toxicity: Potent teratogen in animals. Don't give to pregnant women. Minimal otherwise
Administration: PO
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Class II: opposite of Class I
Prophylaxis only: can’t use in symptomatic patient (no effect on RBC stage)
Can use primaquine to eradicate latent hypnozoites (use if worried about vivax/ovale exposure)
Class III: treatment & prophylaxis (liver stage & asexual stage)
Heme biosynthesis: When Hb is broken down; heme is formed (toxic). Humans & plasmodia (feed on Hb) both have
mechanisms to detoxify
Humans: break down via heme oxygenase to make bilirubin & excrete
Plasmodium: no heme oxygenase: form heme polymers (visible as “malaria pigment” or “hemozoin” in
plasmodia).
Chloroquine blocks this breakdown; heme accumulates; plasmodia die
o Resistance: enhanced efflux mechanisms
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Situation Treatment
Prophylaxis Before, during, 3wks after
Chloroquine if sensitive; malarone, doxycycline, mefloquine if resistant
Add primaquine if exposure to vivax/ovale (test for G6PD 1st)
Mild/moderate infection ORAL
Chlorquine if sensitive
Malarone [or Coartem or quinine (+doxy/tetra/clinda)] if resistant
Add primaquine when recovered if exposed to vivax/ovale (test for G6PD 1st)
Severe illness IV
Quinidine or quinine + (doxy/tetra/clinda)
Add primaquine when recovered if exposed to vivax/ovale (test for G6PD 1st)
Note: only 15-30% US travelers take malaria prophy, docs usually get it wrong
Anti-amebics
3 things amoebae can do:
1. Hang out as cysts (infective form)
2. Turn into trophozoites but hang out in lumen (commensal)
3. Invade as trophozoites (flask shaped ulcers, etc.)
Infection Treatment
Asymptomatic (luminal carrier) Luminal agent only Paromycin, diloxanide fuorate
Symptomatic (tissue invasion) Luminal agent + tissue agent Metronidazole, tinidazole
Pentamidine
pentamidine Mechanism of action: Active transport & accumulation in parasites.
Activity is multifactorial: disorganize mitoDNA, inhibit mito Topo, bind ribosomes, inhibit
phospholipid synth, etc.
Indications: T. brucei, Leishmania, Blastomycosis, Babesia, P. jiroveci.
Aerosolized form recommended for PCP prophylaxis in HIV patients (second line because of
toxicity for Tx behind TMP+SMX)
Toxicity: severe in 55% AIDS pts with PCP. leukopenia, azotemia, hepatitis, unpredictable hypoglycemia
(insulin similarities), others.
Other: Structural analog of synthalin (synthetic insulin)