Antiparasitics Flashcards
Antiparasitic Drugs - General
No vaccines
Commercial incentives limited for many parasitic infections
Parasites often have unique systems that can provide selective targets
Resistance is always a problem
Neglected Parasitic Infections in the US
Trypanosoma cruzi (Chagas Disease) Taenia solium (cysticercosis and neurocysticercosis) Toxocara (Dog and cat roundworms) Toxoplasma gondii (TOrches) Trichomonas (STD)
Parasitic infections associated with HIV
In US: Pneumocystis jirovecii, Toxoplasma gondii, Cryptosporidium
Globally: Malaria, Leishmania, Trypanosoma cruzi
What are the 5 human malaria parasites?
P. falciparum - constant - all RBCs P. vivax - 48 hr - hypnozoites in liver P. ovale - 48 hr - relapsing P. malariae P. knowlesi - 24 hr - zoonotic infections
Malaria parasite life cycle
sporozoites injected by mosquito –> go to liver –> merozoites formed (hypnozoites in vivax and ovale) –> merozoites invade and divide and rupture RBCs –> sexual stages produce gametocytes –> gametocytes taken up by mosquito
True or False: No drug kills malarial sporozoites.
True
Malarial drugs that attack LIVER stages (exoerythrocytic schizonticides)
Primaquine - merozoties and hypnozoites
Atovaquone and Artemisinins - merozoites
Malarial drugs that attack BLOOD stages (erythrocytic schizonticides)
Chloroquine Mefloquine Artemisinins Quinine Doxycycline & tetracycline Clindamycin
Malarial chemoprophylaxis
Prevention: insect repellant, insecticides, bed nets
Awareness
Drugs for PREVENTION of Clinical Disease
Chloroquine [Aralen] Hydroxychloroquine sulfate [Plaquenil] Atovaquone + Proguanil [Malarone] Mefloquine [Lariam] Primaquine Doxycycline
Chloroquine [Aralen]
start 1-2 wk prior
continue 4 wk after
Hydroxychloroquine sulfate [Plaquenil]
start 1-2wk prior
contine 4wk after
Atovaquone + Proguanil [Malarone]
used in all areas
start 1-2d prior
continue 7 days after
Mefloquine [Lariam]
start >2wk early
continue 4wk
TOXIC SIDE EFFECTS
Primaquine
mainly for P. vivax
start 1-2d prior
continue 7 d after
Doxycycline
used in all areas
start 1-2d prior
continue 4 wk
Tx for uncomplicated malaria or unidentified species
Chloroquine sensitive: Chloroquine, Hydroxychloroquine sulfate
Chloroquine resistant:
Atovaquone + Proguanil [Malarone]
Artemether + lumefantrine [Coartem] (NOT READILY AVAILABLE)
Quinine sulfate + Doxycycline or Tetracycline or Clindamycin
Mefloquine [Lariam]
Tx for uncomplicated malaria: P. vivax or P. ovale
CQ sensitive:
Chloroquine
Hydroxychloroquine sulfate + primaquine
CQ resistant (2 drug minimum): Quinine sulfate + doxycycline Tetracycline + primaquine Atovaquone + Proguanil + primaquine Mefloquine + primaquine
Tx for uncomplicated malaria: P. malariae or P. knowlesi
Chloroquine
Hydroxychloroquine sulfate
Sx for complicated malaria
Sx: impaired consciousness/coma, severe normocytic anemia, renal failure, pulmonary edema, etc.
Tx for complicated malaria
IV Quinidine gluconate + doxycycline or tetracycline or clindamycin
[consult cardiologist and experienced physician
monitor: BP, cardiac function, glucose levels (hypotension, widening QRS and/or lengthening QTc interval, hypoglycemia)]
IV Artesunate followed by Malarone, Doxycycline, Mefloquine (if Quinidine gluconate doesn’t work)
Artemisinin
Derived from Chinese wormwood (Artemesia)
Endoperoxide active group
RAPIDLY acting blood schizonticide
No effect on liver stages
active against all species
short half-life
high recrudescence rate after short course
commonly paired with other drugs (ex. mefloquine or lumefantrine)
Artemisinin combination therapy
Artemisinin provides rapid knockdown
Longer half-life component eliminates remaining parasites
Combinations:
Artemether + lumefantrin (Coartem)
Artesunate + mefloquine
Dihydroartemesinin + piperaquine
Artemisinin antimalarial effect is associated with _____
Cmax
concentration dependent killing
Artemisinin derivatives
Artemisinin (insoluble - oral)
Artesunate (water-soluble - oral, IV, IM, rectal)
Dihydroartemisinin (soluble - oral)
Artemether (lipid-soluble - oral, IM, rectal)
Artemisinin adverse effects
well tolerated
nausea, vomiting, diarrhea, and dizziness
EMBRYOTOXIC
Examples of 4-aminoquinilones
quinine, chloroquine, mefloquine, aminoquinoline
Block the polymerization of heme
Hemoglobin metabolism
Malaria parasites ingest hemoglobin from host cell –> hemoglobin is degraded into amino acids and free heme(toxic) –> parasite polymerize heme into hemozoin(nontoxic)
How does chloroquine effect parasite hemoglobin metabolism
chloroquine accumulates in food vacuole and inhibits heme polymerization (heme(toxic) –> hemozoin(nontoxic))
Chloroquine (CQ)
drug of choice for Tx and prophylaxis
oral use, well absorbed, large Vd
half life 3-5d (terminal half-life 1-2mo)
CQ antimalarial effect is associated with _____
T > MIC
opposite of Artemisinin
How did CQ resistance occur
developed in at least 2 foci in P. falciparum
- mutations in PfCRT1 (caused reduced accumulation of CQ)
- over-expression of PfMDR1 (drug transporter)
P.vivax developed resistance later under a different mechanism
Adverse effects of CQ
Usually “very well tolerated”
Pruritus is common (esp in Africans)
Not recommended in IV
CONTRADICTED in psoriasis, porphyria, retinal abnormalities, and myopathy
Antidiarrheal agents KAOLIN AND CALCIUM interfere with CQ absorption
What are some other CQ related compounds
Mefloquine Lumefantrine Piperaquine Amodiaquine Halofantrine Tafenoquine
What substance contains quinine
tonic water
Quinine and Quinidine
rapidly acting blood schizonticide
active against all Plasmodium and Babesiosis
Mode of Action similar to CQ
IV for severe falciparum malaria
oral for uncomplicated “ “
Metabolized by CYP3A4 (can raise levels of warfarin and digoxin; also interact with HIV drugs)
Adverse effects of Quinine
Cinchonism: tinnitus, headache, nausea, dizziness, flushing, and visual disturbances Cardiotoxicity Stimulates uterine contractions Hemolysis Severe hypotension with rapid infusion
Mefloquine [Lariam] Usage
Resistance increasing
Both prophylaxis and Tx
Erythrocytic forms - falciparum & vivax
Adverse effects of Mefloquine
Neuropsychiatric toxicity: seizures, toxic psychosis, and sleep disturbance
What is an example of an 8-aminoquinoline
Primaquine
Primaquine effects
MOA unknown - probably involves ROS Drug of choice for liver stages of vivax and oval (with CQ) gametocidal against all types well absorbed orally some resistance
Adverse effects of Primaquine
too toxic for long term Tx
Contradicted in G6PD deficiency and pregnancy (predisposes to HEMOLYTIC ANEMIA)
Avoid in patients with:
granulocytopenia, methemoglobinemia, receiving myelosuppressive drugs (ex quinidine), or disorders that commonly include myelosuppression
What are 2 types of antifolates
Pyrimethamine and Proguanil
Fansidar [Pyrimethamine-Sulfadoxine]
Folate synthesis inhibitor
slow acting erythrocytic schizonticides
Sulfadoxine inhibits DHPS in malaria (can’t make dihydrofolic acid)
Pyrimethamine and Proguanil inhibit DHFR (can’t make THF)
overall decreases the formation of purines for DNA/RNA
Other uses of antifolates
Toxoplasmosis (Pyrimethamine + sulfadiazine (clindamycin can replace sulfadiazine))
Pneumocystis (SxT aka Bactrim; Atavaquone is alternative)
Use of Antifolates
Use of single antifolates is not recommended (resistance develops easily)
Synergistic effect
combination chosen b/c of matching pharmacokinetics (both have long half-lives)
Resistance is spreading rapidly (no longer recommended)
Malarone
combination of proguanil and atavaquone
Atavaquone MOA: disrupts mitochondrial electron transport
Tx and prophylaxis usage
Generally well tolerated (TAKE WITH FOOD)
Atavaquone is alternative therapy for P. jiroveci
Antibiotics used as antimalarial drugs include
Tetracycline, doxycycline, and clindamycin are blood schizonticides
They target components of the apicoplast
Doxycycline commonly paired with quinine or quinidine for Tx for falciparum
Doxycycline is used for chemoprophylaxis in mefloquine resistant areas
Drugs for Anaerobic Parasites
Metronidazole used for: E. histolytic, Giardiasis, trichomoniasis
Kills trophozoites but not cysts
usually followed by luminal drug to eliminate asymptomatic infection
may target parasite DNA??
Tinidazole is a similar drug with less toxicity
Metronidazole and alcohol
Metronidazole inhibits acetaldehyde dehyrdrogenase –> acetaldehyde –> hypotension. nausea, vomitting, discomfort
What is Iodoquinol
luminal amebicide low bioavailabilty sole agent in "asymptomatic" carriers combine with metronidazole for amebic dysentery kills trophozoites
What is Pentamidine
parental administration
mechanism unknown
highly toxic
First line agent for West African trypanosomiasis (alternative for visceral leishmania and pneumocystosis)
What is Nifurtimox
Most commonly used for T. cruzi MOA unknown (generate ROS??) reduces severity of acute phase (unlikely to completely eliminate parasite) orally available 3-4mo course of Tx Toxicity common
Miltefosine
phospholipid analog approved for use against visceral leishmaniasis 28 daily doses - almost 100% cure rate MOA unknown side effects tolerable TERATOGENIC - avoid during pregnancy
What is used to treat Giardia and Cryptosporidium
Nitazoxanide
What is used to treat T. cruzi
Nifurtimox or Benznidazole
What is used to treat T. brusei
West African - Early: Pentamidine; Late: Eflornithine
East African - Early: Suramin; Late: Melarsoprol(not good)
