Antifungals And Anti-Parasitics

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Polyene Macrolide Antifungals

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Macrolide antibiotics ironically produced by soil fungi. Low solubility, high toxicity.
MOA: binds to ergosterol on fungal cell wall, and inserts a pore.
Members: amphotericin B, Nystatin

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Amphotericin B

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Class: polyene macrolide
Uses: systemic fungal infxns
Sides: Most toxic antibiotic in current use. Acute hypotension, seizures, fever; chronic renal failure (tubular acidosis) Use slow infusion, NEVER loading dose.
PK: insoluble; prepared in detergent (desoxycholate) or lipid-drug formulations. Can't cross BBB, give intrathecally for meningitis.

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Azole Antifungals

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Imidazoles (2N) and triazoles (3N)
MOA: inhibits synthesis of ergosterol (14α-demethylase). May thus antagonise polyene macrolides.

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Ketaconazole

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Class: Imidazole antifungal
Uses: broad-spec anti-dermatophyte, rarely used as antifungal today, usually as endocrine drug.
PK: po, requires acid pH for solubilisation, don't take antacids.
Sides: (-)P450 (extensively met'd by it; torsade de pointes if taken with antihistamines), (-)adrenal sex steroid syn. Hepatitis rare.

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Fluconazole (Diflucan)

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Class: triazole antifungal.
Pk: water soluble, absorbed GI, diffuses across BBB.
Met: renal
Uses: candidiasis
DOC: fungal meningitis esp. in AIDS.
Sides: nausea, vomitting, headaches, diarrhoea, but gen. v. safe, least P450 effect of antifungals.

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Itraconazole

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Class: triazole antifungal
Uses: nonmeningeal histoplasmosis, blastomycosis.
DOC: histo in AIDS, after stabilisation by amphotericin B.; nail/dermatophyte infxns
Sides: gen. v. few; rare GI upset, nausea, vomitting. Rare hepatotoxic. May (-)P450.
Contra: CHF, due to neg. inotropic effects.

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Synthetic allylamines

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Low MW synthetic antifungals
MOA: inhibits squalene-2,3-epoxidase, thus blocking ergosterol syn, and also causing acc. of toxic squalene.
Ex: terbinafine

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Terbinafine

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Class: synthetic allylamine antifungal.
Uses: tinea corporis, cruris, pedis.
Contra: CHF due to neg. inotropic effects.
Notes: replaces griseofulvin.

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Flucytosine

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Class: antimetabolite antifungal
MOA: prodrug 5FC → 5-FU in fungi, (-)thymidine synthetase.
Uses: in combo w. amphotericin B for systemic or meningitis, alone for chromoblastomycosis.
PK: crosses BBB, well absorbed, little met.
Sides: depress bone marrow if 5-FU leaks out; anaemia.

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Echinocandins

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Ex: Caspofungin
MOA: non-competitive inhibitors of Candida & Aspergillis cell wall component. (FKs1p subunit of glucan synthase complex, inhibiting β-(1,3) glucan polysaccharide syn.

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Caspofungin

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Uses: Only iv antifungal against C. albicans, 2nd line against invasive aspergillis.
PK: large lipopeptide; not absorbed GI.
Contra: cyclosporines; co-administration causes ↑'d caspofungin levels, may mess up liver.
Sides: histamine release, phlebitis, fever, headache, hypokalaemia. Rare: anaphylaxis, haemolysis.

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Griseofulvin

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Class: antibiotic fungistatic
MOA: binds to keratin, microtubules of fungi. Deposited in keratin precursor cells, must "grow out" old infxn.
Uses: HK foot, mycotic skin, nail, hair diseases.
Notes: replaced by itraconazole and terbinafine.
PK: ↑ absorption if taken w. fatty meal. ↑P450 (cf. rifampin)
Sides: severe headaches, neuritis, lethargy, fatigue, syncope. Disulfiram-like effect. Possible leukopaenia, neutropaenia, photosensitivity (high doses).

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Antimalarials

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MOA: blocks Hb processing in Plasmodium, causing haeme toxicity.
MOR: efflux
Categories: primaquine (kills dormant P. vivax/ovale), all others (kill only erythrocytic forms)
Method: 1.) prophylaxis 2.) self-medication 3.) physician Tx.

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Chloroquine

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Class: antimalarial
THE prototype
t1/2: 30-60d, wkly dose for prophylaxis.
Active: erythrocytic forms of all plasmodium spp.
Notes: very safe for kids and pregnant women.
Adverse: gen. well-tolerated. Pruritis (common, esp. darker skin); nausea, headache, blurred vision (occasional); confusion, hypotension, exfoliate dermatitis (rare)
Contra: Psoriasis, prophyria, retinal abnormalities, liver diseased, G6PDH deficiency (haemolysis), Ca2+/Mg2+ suppl.

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Mefloquine

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Class: antimalarial
Activity: erythrocytic plasmodia
t1/2: 20d, wkly dosing for prophylaxis
Resistance: ↑g in SE Asia
Adverse: CNS toxicity, rare: seizures, hallucinations, severe anxiety. Arrythmias
Contra: epilepsy, psychiatric disorders, cardiac conduction problems, liver disease.
Notes: gen. safe for pregnancy, 1° substitute for chloroquine.

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Doxycycline

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Class: tetracycline antibiotic/anti-malarial
Activity: erythrocytic forms of plasmodia.
t1/2: short, daily dose for prophylaxis.
Uses: combo w. quinidine for severe P. falciparum malaria. 2nd line for mefloquine resistent strain in SE Asia.
Adverse: GI distress, yeast infxns, photosensitivity.
Contra: pregnancy, children <8, divalent ion suppls.

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Atovaquone-Proguanil

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Class: antimalarial
Use: mefloquine alt.
Activity: erythrocytic plasmodia spp.
t1/2: short; daily dose for prophylaxis.
Adverse: abdmoinal pain, nausea, vomitting, headaches, dizziness.
Contra: children, pregnancy/nursing, kidney disease, rifampin (↓s [atovaquone])

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Atovaquone

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MOA: (-) plasmodia ATP syn. and ox-phos. Active against other protozoa.

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Proguanil

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Antifolate antimalarial
MOA: progrun transformed by P450 to active cycloguanil, inhibits folic acid syn.

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Primaquine

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Class: schizonticidic antimalarial
Activity: only antimalarial against dormant hepatic P. vivax/ovale schizonts. NOT active against erythrocytic forms, always use in combo.
Adverse: nausea, abdominal cramps, headache. Rare: arrhythmias, leukopaenia, leukocytosis, agranlocytosis.
Contra: G6PDH deficiency (causes HUS, methaemoglobinaemia), pregnancy, marrow suppression.

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Metronidazole

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Class: antiprotozoal
Activity: Giardia, Entamoeba, Trichomonas, anaerobes, C. difficile.
MOA: reactive intermediates disrupt DNA sxr, repair, syn.
Adverse: (-)P450,
common: dry mouth, metallic taste, nausea, headache. Ocassional: GI distress. Rare: peripheral neuropathy.
Contra: 1st trimester pregnancy, alcohol (disulfiram-like rxn), P450 drugs (warfarin).

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TMP-SMX

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Class: antimetabolite/folate antibiotic/antiprotozoal
Uses: cyclospora, PCP in AIDS.
PK: (-)P450
Adverse: GI distress, photosensitivity, AIDS: fever, rashes, diarrhoea, leukopaenia; hypersensitivity to sulfonamides. Rare: hepatotoxicity.
Contra: 3rd trimester pregnancy (kernicterus bilirubin encephalopathy), G6PDH deficiency (hepatotoxicity).

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Niclosamide

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Class: anticestode (tapeworms)
MOA: (-) anaerobic met., paralysing cestode, detaching scolex.
PK: not absorbed GI, high conc. w/o toxicity.
Spectrum: most cestodes, but not ovicidal
Route: single dose po
Adverse: avoid alcohol, no major side effects.
Notes: no longer available in U.S.

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Mebendazole

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Class: benzimidazole antinematode (roundworms)
MOA: uncouples ox-phos, binds tubulin, (-) microtubule polymerisation. Nematodes can't met., drug accumulates.
Spectrum: adults/eggs of most nematodes, hookworms, alt. for trichinosis.
Adverse: abdominal discomfort/diarrhoea possible.
Contra: 1st trimester pregnancy.

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Pyrantel

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Class: anti-nematode
MOA: depolarises helminth mm, (-) AChE. Spastic paralysis.
PK: poorly absorbed in GI.
Spectrum: pinworms, hookworms.
Contra: infants, pregnancy
Adverse: (Rare) headaches, dizziness, drowsiness, GI irritation.

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Diethylcarbamazine

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Class: anti-nematode piperazine derivative
DOC: filariasis, loiasis, tropical eosinophilia.
MOA: immobilisation of worm mm, changes worm surf. mem, makes them more susceptible to host defenses.
PK: well-absorbed from gut
Contra: onchocerciasis (worsens ocular lesions, Mazzotti rxn)
Adverse: fever, rashes, tachycardia, headache, Mazzotti rxn.

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Ivermectin

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Class: anti-nematode
MOA: GABA, Glu-gated Cl- chs = tonic paralysis of worm.
PK: rapidly absorbed GI, effluxed out of CNS, can't use for meningitis
Spectrum: broad; nematodes, insects, ascarine parasites.
DOC: onchocerciasis, strongyloidiasis, filariasis.
Contra: pregnancy, children <5 yo

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Mazzotti Reaction

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Adverse rxn seen with diethylcarbammazine and more rarely, ivermectin.
Path: due to killing of microfilariae; begins day following single dose, peaks on 2nd day.
Sxs: Fever, headache, dizziness, weakness, rash, pruritis, jnt/mm pain, tachycardia, peripheral oedema.

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Praziquantel

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Class: anti-cestode/trematode
MOA: causes Ca2+ influx in worm by changing mem. perm., causing spastic paralysis.
DOC: schistosomiasis.
Spec: not ovicidal, but otherwise broad.
Adverse: nausea, vomitting, dizziness, drowsiness, abdominal discomfort. Onset in hours. Better tolerated in children.
Contra: pregnancy, ocular cysticerosis (irreversible eye damage, spinal neurocysticercosis)