Antiparasitic Drugs

List the drug targets of Antiprotozoal and Antihelminthic

Antiprotozoal drugs Targets

• Malaria

• Amebiasis / giardiasis / trichomoniasis

• Toxoplasmosis

• Other protozoa

Antihelminthic drugs Targets 

• Nematodes: Roundworms

• Cestodes: Tapeworms

• Trematodes: Flukes

[REVIEW] Protozoa vs Helminths

Why do Antibiotics Also Treat Protozoal Infections

Describe the different malaria Species and the disease they create. Describe the 3 stages in their life cycle

• Malaria species

  • P. falciparum: Most severe malaria

  • P. vivax / P. ovale: forms dormant liver hypnozoites

  • P. malariae: Chronic low-level infection 

  • P. knowlesi: Zoonotic malaria w/ rapid cycle

• Life Stages:

  • Hepatic stage: 

    • Initial liver infection after mosquito bite

  • Erythrocytic stage: 

    • RBC infection -> clinical disease

  • Hypnozoite stage: 

    • Dormant liver form in vivax/ovale

Describe Antimalarial Drugs

• Two Classes?

• List the drugs in the first class and describe them

• List the drugs in second class and describe them

Two Classes:

• Blood schizonticides

  • Treat erythrocytic malaria

• Tissue Agents:

  • Target Hepatic Forms

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Schizonticides

• Chloro-quine: 

  • Blood-stage therapy

• Quin-ine / quini-dine: 

  • Older agents

• Meflo-quine: 

  • Blood schizonticide

• Art-emisinin combinations: 

  • Major modern malaria therapy

• Atova-quone-pro-guanil: 

  • Useful oral combination option

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Tissue agents

• Prima-quine: 

  • Eradicates dormant liver hypnozoites

• Tafen-oquine: 

  • Long-acting anti-hypnozoite agen

Describe CHLOROQUINE

• MOA

• Clinical Importance

• Adverse Effects

CHLOROQUINE

• MOA:

  • Blocks heme polymerization in parasite vacuole -> toxic free heme accumulation

• Clinical Importance:

  • Historically major antimalarial

    • Resistance limits modern use

    • (Still useful in chloroquine-sensitive regions)

• Adverse effects

  • GI toxicity: 

    • Nausea, vomiting, abdominal upset

  • Pruritus: 

    • Classic adverse effect

  • Retinopathy: 

    • Risk w/ long-term exposure

Describe QUININE, QUINIDINE, MEFLOQUINE

• MOA

• Clinical Importance

• Adverse Effects

QUININE, QUINIDINE, MEFLOQUINE

• MOA:

  • Disrupt parasite heme detoxification

• Clinical Importance:

  • Quinine/quinidine: 

    • Older, Imp. in severe/resistant malaria settings

  • Mefloquine: 

    • Prophylaxis or treatment 

• Adverse Effects:

  • Quinine/quinidine: 

    • cinchonism,

    • hypoglycemia

    • arrhythmias

  • Mefloquine

    • neuropsychiatric toxicity

      • (mood, sleep, & CNS effects).

Describe Cinchonism

• Cause

• Symptoms

• Severe effects?

• Takeaway?

Describe ARTEMISININ

• Origins

• MOA

• ACT

  • Drugs Used?

  • Clinical Use?

ARTEMISININ

• Origins:

  • From Artemisia annua (sweet wormwood)

  • Discovered in Chinese antimalarial research

    • (Tu Youyou won the 2015 Nobel Prize)

• MOA:

  • Activated by iron/heme in parasite → free radicals → rapid parasite killing

• ACT (Artemisinin-based combination therapy) 

  • Drugs Involved:

    • Artemisinin + partner drug = Improve treatment sucess + lower resistance

  • Major Clinical Use:

    • uncomplicated falciparum malaria

Describe PRIMAQUINE & TAFENOQUINE

• Targets

• MOA

• Adverse Effects

PRIMAQUINE & TAFENOQUINE

• Targets:

  • hepatic hypnozoites + other liver-stage parasites

    • P. vivax and P. ovale

• MOA:

  • Gen. Rxt. oxidative metabolites -> Mitochondrial dysfunction -> Parasite + Dormant form death -> no relapse

• Adverse Effects:

  • Oxi. Stress in RBCs -> Hemolysis

    • w/ G6PD deficiency

1. Describe Atovaquone-proguanil

   • Clinical Use

   • MOA

   • Combo Effect

2. Describe the uses of Doxycycline/Clindamycin

Atova-quone-pro-guanil

• Clinical Use:

  • Treatment and prophylaxis

• MOA

  • Atovaquone

    • Inhibits mitochondrial ETC

  • Proguanil

    • DHFR inhibition

• Combo effect: 

  • Better efficacy, less resistance

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Doxy-cycline

• Prophylaxis or combination use

Clinda-mycin

• Alternative combination partner

Describe NITROIMIDAZOLE DRUGS

• Targets

• Types

• MOA

• Why aerobes are less susceptible: 

NITROIMIDAZOLE DRUGS

• Targets:

  • anaerobic bacteria & selected protozoa

• Types:

  • Metro-nida-zole 

  • ti-nida-zole

• MOA:

  • Nitro group Reduction via Electon-transport proteins -> toxic free radical Formation → damage DNA + critical macromolecules 

    • Low-redox conditions in anaerobes favor drug activation

• Why aerobes are less susceptible: 

  • O2 interferes w/ activation + detoxifies reactive intermediates

Describe MEDTRONIDAZOLE

• Uses

• Target

• Adverse EFfects

MEDTRONIDAZOLE

• Uses:

  • Anaerobic coverage

• Target 

  • Amebiasis, giardiasis, trichomoniasis

• Adverse effects

  • Metallic taste, GI upset

  • Prolonged use: Peripheral neuropathy

  • Disulfiram-like reaction with alcohol

NOTE: Classic antiparasitic + anaerobe drug

Describe LUMINAL AMEBICIDES

• Usage

• Types/MOA

• Usage:

  • Use for Luminal Organisms

  • For Clear Intestinal Colonization after treatment of invasive disease

• Types/MOA:

  • Paro-mo-mycin

    • aminoglycoside antibiotic (binds 30S)

  • Iodo-quinol

    • Disrupts parasite metabolism (unclear mechanism)

Describe NITAZOXAMIDE

• Class

• Clinical Usage

• MOA

NITA-ZO-XAMIDE

• Class:

  • Broad antiprotozoal drug

• Clinical Usage:

  • protozoal diarrhea therapy

  • Giardia, Cryptosporidium

  • Alt. or Adjunts 

• MOA:

  • Inhibits Pyruvate:ferredoxin oxidoreductase (PFOR)–dependent electron transfer reaction 

    • Disrupts anaerobic metabolism

Describe TOXOPLAMOSIS

• Importance

• Treatment?

  • Classic regimen =?

  • MOA?

  • Synergy Effects?

• Adverse Effects?

TOXOPLAMOSIS

• Importance:

  • in congenital & immunocompromised disease

• Treatment

  • Classic Regimen = Pyri-methamine + sulfa-diazine + leuco-vorin

  • MOA:

    • Pyrimethamine: DHFR inhibitor

    • Sulfadiazine: Dihydropteroate synthase inhibitor

    • Leucovorin: Host marrow rescue

      • not antiparasitic

  • Synergy:  Sequential folate antagonism

• Adverse Effects:

  • Bone marrow suppression

Describe Cyclospora cayetanensis

• Diagnosis, Treatment, Prevention?

List the treatment for:

• Leishmaniasis

• Trypanosomiasis

• Babesiosis

• Leishmaniasis

  • Stibo-gluconate, 

  • milte-fosine, 

  • amphotericin B

• Trypanosomiasis

  • Ni-fur-timox, 

  • Ben-zni-dazole,

  • Sura-min

  • melar-soprol, 

  • eflor-nithine

• Babesiosis

  • Ato-vaquone + azith-romycin

Describe ANTIHELMINTHIC DRUGS

• Class/types/MOA

  • Benzimidazoles

  • Neuromuscular/paralytic agents:

  • Praziquantel

  • Niclosamide

ANTIHELMINTHIC DRUGS

Classes/Types/MOA:

• Ben-zi-mi-dazoles

  • MOA: impair parasite microtubule function

  • Types: Al-bend-azole, Me-bend-azole

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• Neuromuscular/paralytic agents:

  • MOA: Immobilize Worms 

  • Types:

    • Pyrantel pamoate: 

      • Causes depolarizing neuromuscular paralysis

    • Iver-mectin

      • Enhances inhibitory neurotransmission

    • Di-ethyl-carbamazine

      • filarial infections

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• Pra-zi-quantel

  • MOA: Increases calcium permeability -> paralysis + tegument injury

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• Niclosamide: Tapeworm drug

Describe BENZIMIDAZOLE CLASS Drugs

• Targets

• MOA

• Types/Targets

• Adverse Effects

Targets:

• Broad nematode activity

MOA:

• Microtubule inhibition ->  Decreased glucose uptake 

  • affinity for β-tubulin worms > humans

Types/Targets:

• Al-bend-azole

  • intestinal worms + Cestodes (selected tissue)

• Me-bend-azole

  • Classic for many intestinal nematode infections

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ADVERSE EFFECTS

• GI upset

  • Nausea, abdominal discomfort, or mild diarrhea 

• Liver Effects

  • Transaminase elevation 

  • Hepatotoxcitiy

    • Greater concern with higher doses or longer treatment.

• Bone marrow suppression

List the clinical usage of ALBENDAZOLE

Describe PYRANTEL PAMOATE

• Uses

• Targets

• MOA

PYRANTEL PAMOATE

• Usage:

  • Classic antihelminthic for common intestinal nematodes

• Targets:

  • Pinworm, roundworm, hookworm

• MOA:

  • neuromuscular blockade and paralysis of worms

Describe IVERMECTIN

• Usage

• Targets

• MOA

IVERMECTIN

• Usage:

  • High-yield antiparasitic drug

• Targets:

  • strongyloides, 

  • river blindness (onchocerciasis) 

  • scabies Ectoparasite 

• MOA:

  • Increases Cl- conductance in nerves/muscles -> paralysis

Describe DIETHYLCARBAMAZINE

• Usage

• Targets

DIETHYLCARBAMAZINE

• Usage:

  • Classic antifilarial drug 

    • tissue-dwelling nematode 

• Targets:

  • Wuchereria bancrofti

    • lymphatic filariasis

  • Brugia malayi

    • lymphatic filariasis

  • Loa Loa

    • African eye infection

NOTE:  Inflammatory pearl: Parasite killing can provoke host inflammatory reactions

Describe PRAZIQUANTEL

• Usage

• Targets

• MOA

PRAZIQUANTEL

• Usage:

  • many trematodes & cestodes

  • Classic fluke & tapeworm drug

• Targets:

  • schistosomiasis

• MOA:

  • Increases helminth Ca²⁺ permeability  -> Paralysis/Death