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Flashcards in Anti-Parasitics Deck (16):
1

Describe the major classes of antiparasitic agents: anti-helmminths

Benzimidazoles (Albendazole)
■ inhibit polymerization of worm B-tubulin
■ Active Metabolite well distributed to tissues

Avermectins (ivermectin)
■ potentiate the glutamate-gated chloride channels unique to nematodes
■ → toxic paralysis
■ (affects developing filarial worm larvae and prevents egress of microfilariae from the uterus of the adult worm)

Praziquantel (Biltricide, Distocide)
■ bimodal and dose dependent.:
■ Low: induces muscular activity and spastic worm paralysis
■ High: targets the worm tegument; causes Ca blebbing of the surface
● increase susceptibility to immune response

2

Describe the major classes of antiparasitic agents: anti-protozoals

Metronidazole
■ pro-drug: reduction at extra cyclic nitro group (preferentially occurs in anaerobic bacteria)
■ → highly reactive molecule that inflicts free radical damage on DNA and other macromolecules

3

List the major anti-malarials

Quinine
Chloroquine
Primaquine
Mefloquine
Chloroguanide
Atavoquone
Artemisinin

4

Explain the differences among blood schizonticides, tissue schizonticides, and
gametocytocides.

Blood schizonticides
○ includes most of the antimalarial drugs
○ act on the erythrocytic stage of the infection to block schizogeny and terminate a clinical attack (clinical cure)
○ for chemoprophylaxis by effecting a suppressive cure

Tissue schizonticides
2 types
■ Acts on the primary tissue schizonts within the liver to prevent initiation of clinical malaria (Chloroguanide)
■ Acts on the latent tissue forms to prevent relapse of P. vivax and P. ovale. (Primaquine)

Gametocytocides
○ Show activity against the sexual forms of the parasite; none used clinically

5

Albendazole

● Roundworms/Nematodes (Ascaris, Hookworms, Whipworms, Pinworms, Trichinosis [most effective early, before migration to muscle]
● Tapeworms/Cestodes: cysticercosis (pork tapeworms), Zoonotic tapeworms (Echinococcus granulosus and Echinococcus multilocularis) (often with surgical resection)

MOA:
■ inhibit polymerization of worm B-tubulin
■ Active Metabolite well distributed to tissues

NOT use if pregnant, cirrhosis

6

Ivermectin

● Roundworms/Nematodes (Threadworms, larvae of filarial worms, Threadworms, onchocerciasis)

MOA:
■ potentiate the glutamate-gated chloride channels unique to nematodes → toxic paralysis
■ (affects developing filarial worm larvae and prevents egress of microfilariae from the uterus of the adult worm) = kills larvae but not adult worms

NOT use if: compromised BBB (acted on by CNS P-glycoprotein efflux pumps)

7

Praziquantel

Tapeworms; all except echinococcosis and cysticercosis
○ Beef tapeworms, Pork tapeworms (incl: cysticercosis), Fish, Dwarf tapeworms,
Flukes: Blood flukes, Lung flukes, Liver flukes (C. sinenis and O. viverrini), Intestinal flukes

MOA: Increases cell membrane permeability, Ca- dependent, disintegrates schistosome integument

NOT use for nematodes

8

Metronidazole

■ pro-drug: reduction at extra cyclic nitro group (preferentially occurs in anaerobic bacteria)
■ → highly reactive molecule that inflicts free radical damage on DNA and other macromolecules

Uses: protozoa, T. vaginalis, amebiasis, giardia

Side effects: Headache, nausea, dry mouth, anorexia, diarrhea, cramping, neurotoxicity, do NOT combine with EtOH

9

Quinine

MOA
● Raises vacuolar pH, inhibiting polymerization of heme into hemozoin

Use
● Malaria, blood schizonticide, IV for cerebral malaria

Toxicity
● Cinchonism: ringing ears, headaches, nausea and blurred vision
● Hypersensitivity
Blackwater fever = severe form - massive hemolysis
● Hypoglycemia
● decreases the excitability of the motor end plate of skeletal muscle

10

Chloroquine

MOA
● Same MOA as quinine: Raises vacuolar pH, inhibiting polymerization of heme into hemozoin
● more effective and less toxic
● Resistance becoming widespread

Use
● Malaria, Blood schizonticide - chemoprophylaxis and treatment.

NOT use if: liver disease, G6PD deficiency

Toxicity
● high doses → CV effects (HTN and ECG abnormalities)
● Over 5 g can be lethal.
● Contraindicated in liver disease and G6PDH deficiency.

11

Primaquine

MOA
● Oxidative damage, gametocidal

Use
● latent tissue schizonts (chronic P. vivax and P. ovale)

NOT use if: G6PD deficiency, pregnant and breastfeeding women

Toxicity
● Methemoglobinemia

12

Mefloquine

MOA
● concentrated in food vacuoles, raises pH, and causes swelling, but it does not inhibit heme polymerization
● May form toxic complexes with heme

Use
● DOC: prophylaxis in regions of chloroquine resistance
● Given once weekly
● Treatment of chloroquine resistant malaria.

Toxicity
● Well tolerated, more SE when used as treatment
● Mild: nausea, dizziness, nightmares, fatigue, and lassitude
● Rare: Seizures and acute psychosis (contraindicated in those with psychiatric history)
● Decreases efficacy of oral typhoid vaccine
● Not approved for pregnant women

13

Chloroguanide

MOA
● Inhibits dihydrofolate reductase- thymidylate synthetase

Use
● Prophylaxis of malaria, active against tissue schizonts
● Can also terminate clinical attacks
● Combo with atovaquone = malarone

NOT use if: Pregnant or breastfeeding women, infants

Toxicity
● Very safe at therapeutic dose

14

Atavoquone

MOA
● Ubiquinone analog; selectively interfering with mitochondrial electron transport

Use
● prophylaxis and treatment of chloroquine-resistant malaria
● Used with chloroguanide = malarone

NOT use if: Pregnant or breastfeeding women, infants

Toxicity
● rash, fever, vomiting, diarrhea, and headache
● vomiting and diarrhea - from inadequate absorption
● 20% Dose-related maculopapular rash - does not become severe with continued therapy.

15

Artemisinin

(Qinghaosu)

MOA
● endoperoxide bridge or “warhead” is essential for activity
○ form a complex with ferrous non-heme iron
○ → formation of toxic, carbon-centered free radicals and alkylation of macromolecules

Use
● With lumefantrine for CQ-resistant malaria
○ single dose cures 90% of patients within 72 h
● Expensive so reserved for chloroquine-resistant and multidrug-resistant

Toxicity
● No dose-limiting toxicities in humans.

16

Describe mechanisms through which protozoa develop resistance to chemotherapy, with an emphasis on malaria.

CQ resistance - energy-dependent efflux of CQ from food vacuoles (links all CQ resistant strains)
○ Blocks by Ca channel blocker verapamil

P. falciparum chloroquine-resistance transporter gene (PfCRT) = target for mutations that confer resistance
○ transporter protein with 10 transmembrane domains localized to digestive vacuole
○ all CQR strains of P. falciparum contain a lysine to threonine substitution at amino acid 76 (K76T)
○ PfCRT mutations are specifically associated with CQR (not quinine, mefloquine)

No PvCRT mutations found in CQR P. vivax. (ie they use different mechanism)