Anti-parasitics Flashcards
What are the major, potentially fatal parasitic infections?
Malaria
Schistosomiasis
Trypanosomiasis (Sleeping sickness)
Dengue Fever
What are the major protozoa infections?
Amebiasis
Giardiasis
Trichomoniasis
What are the major helminth infections?
Ascariasis
Pinworm
Hookworm
What are the major opportunistic parasitic infections?
Toxoplasmosis
Cryptosporidiosis
Pneumocystis carinii pneumonia
What are the four categories of anti-parasitic drug MOAs?
- Target enzyme or protein unique to parasite
- Enzyme or protein indispensable to parasite
May share with host
host has alternative metabolic pathway - Different Pharmacology
homologous proteins bind with different affinity - Selectively concentrated in parasite
MOA, selectivity, resistance and elimination of Nitroimidazoles (Metronidazole)
Pro-drug targets enzyme (Pyruvate:ferrodoxin oxidoreductase) unique to the parasite
Target anaerobic organisms
Aerobic respiration in host regenerates parent drug
Resistance through down regulation of enzyme
Rapidly absorbed and distributed into tissues and body fluids
Metabolites: increased half life – retain activity (50% of parent drug)
Eliminated predominantly in urine
Which infections or conditions are treated with metronidazole?
Giardiasis
Severe amebiasis (systemic forms of E. histolytic)
Trichomoniasis (treat all partners)
Pseudomembranous colitis (replaces vancomycin)
Other anaerobic bacteria (peptic ulcers Helicobacter pylori)
What are the adverse reactions and contraindications of metronidazole?
Alcohol (Disulfram-like reaction) Headache and nausea Peripheral neuropathy (long term) First trimester of pregnancy Inducers of hepatic enzymes Hepatic disease Renal dysfunction Existing or development of CNS abnormalities increase levels in CSF
Drug class, uses, administration, and MOA of Paromomycin
Aminoglycoside antibiotic
Therapeutic Use:
Asymptomatic luminal amebiasis
Cryptosporidiosis (AIDS patients)
Visceral and cutaneous Leishmanias
Mechanism:
Oral administration - little systemic absorption
Concentrated in parasite in gut
Inhibits protein synthesis - binds to A-site of ribosome
Treatment of toxoplasmosis
Anti folate combinations that selectively targets parasite enzymes
(50% of all patients show limiting sensitivity to sulfonamides
Significantly higher in AIDS patients)
What are the effects of SMX-TMP and why are they considered synergistic?
Sulfonamides inhibit Dihydropteroic Acid Synthase
Trimethoprim inhibits Dihydrofolate Reductase
Both ultimately inhibit nucleic acid and protein synthesis
They are synergistic because dihydropteroic acid is a precursor of dihydrofolate. Inhibiting its formation makes the later inhibition of dihydrofolate reductase more effective.
What is the mechanism and uses of pentamidine?
Mechanisms (differ by species):
Concentrated in sensitive strains
Pyrimidine salvage pathway
Inhibits SAM-decarboxylase
inhibits polyamine biosynthesis
disrupts DNA structure and function
Binds to minor groove of DNA
inhibits protein synthesis
Inhibits type II topoisomerase
inhibits DNA replication
Interferes with glucose metabolism
Uses:
P. carinii pneumonia (Alternative to TMP-SMX)
West African Trypanosomiasis T. bruce gambiense
(Not effective in T.brucei rhodesiense (EAST) - very early infection of CNS)
Visceral Leishmanias
kala-azar - L. donovani
Benzimadazoles MOA
Inhibit microtubule formation by binding to beta-tubulin and prevent formation of alpha/beta dimers
Selectively binds to parasite tubulin 100x better than to human tubulin
Widespread resistance due to single point mutation Phe200 -> Tyr
Therapeutic uses of benzimadazoles
Mebendazole: Mixed Nematode infections Enterobiasis (pinworm) Ascariasis (common roundworm) Trichuriasis (whipworm) Hookworm (Necator americanus and Ancylostoma duodenale) Albendazole: Nematode infections Ascariasis, Enterobiasis, Hookworm Prophylaxis of Filariasis with Ivermectin or Diethylcarbamazine
MOA and therapeutic use of pyrantel pamoate
Mechanism: Only given orally - very poor absorption Concentrates in parasite Acetylcholine receptor agonist Complete spastic paralysis of worm (and host if given IV)
Therapeutic Use:
Ascariasis (roundworm)
Enterobiasis (pinworm) DOC
Hookworm infections
MOA and therapeutic use of praziquantel
Mechanism
Ca2+ ionophore - induces paralysis, detachment, excretion
Induces tegmental damage - activates immune system
Therapeutic Use
Cestode (tapeworm)
Trematode (flukes)
MOA and therapeutic use of chloroquine
Mechanism: Concentrates in food vacuoles Inhibits Heme polymerization Inhibits peroxidase and catalase activity Generates oxidative stress
Therapeutic Use: Erythrocytic stages of P. vivax P. ovale P. malariae CQ sensitive P. falciparum
MOA and therapeutic use of quinine
Mechanism:
Inhibits parasite feeding mechanism
Generates oxidative stress
Therapeutic Use:
Treatment and cure of erythrocytic stages of
chloroquine resistant and MDR P. falciparum malaria
MOA and therapeutic use of mefloquine
Mechanism:
Generates oxidative stress in same way as chloroquine
Therapeutic Use:
Alternative for treatment of erythrocytic
stages of chloroquine resistant and
MDR P. falciparum
CDC recommends against use US Army replaced use of Mefloquine with Doxycycline In Sept 2013 – considered a court martial offence to prescribe
MOA and therapeutic use of Malarone - Proguanil with Atovaquone
Mechanism:
DHFR Inhibitor
Increases efficacy of Atovaquone to collapse proton gradient
Therapeutic use:
Malaria caused by P. falciparum (as Malarone)
P. carinii pneumonia (in patients who cannot tolerate TMP-SMX or pentamidine IV)
Toxoplasma gondii
MOA and therapeutic uses of Primaquine
Mechanism of Action:
Uncertain
Inhibit electron transport chains
Therapeutic Use
Latent forms of P. vivax and P. ovale.
Only drug active against latent hepatic forms
MOA and therapeutic uses of Artemisinin
Mechanism:
Interacts with heme to generate reactive oxygen species
Therapeutic use:
Arthemeter Combination Therapy (ACT) now recommended as primary treatment for multi-drug resistant P. falciparum in endemic areas
Used in conjunction with lumefantrine (chloroquine analogue), sulfadoxine-pryimethamine
Clinical cure rates of ~ 90% in P. falciparum
Prophylaxis of chloroquine sensitive malaria
Chloroquine Phosphate(oral)
Primary and alternative treatment of chloroquine sensitive malaria
Primary:
Chloroquine Phosphate
Alternative: Chloroquine hydrochloride(IV)
Primary and alternative prophylaxis of MDR malaria
Primary:
Atovaquone/proguanil or Doxycycline
Alternative:
Mefloquine
Primary and alternative treatment of MDR malaria
Primary: Quinine sulfate (ORAL) Quinidine gluconate (IV) plus Tetracycline or plus pyrimethamine-sulfadoxine or plus clindamycin plus Primaquine Phosphate for P. vivax
Alternative:
Atovaquone/proguanil (Malarone)
or
Mefloquine
