Antiparasitics: antiprotozal drugs Flashcards
Trypanosoma cruzi is also called ….
its transmitted by …
chagas disease
-rejuvid bug transmits it - bug defecates on skin and then later person itches the fecal matter into the skin
Taenia solium, aka …
it causes …
pork tapeworm
-causes cysticercosis and neurocyticercosis
Toxicara is typically a ____ infection
-its ____ ___ worm
zoonotic
- dog and cat roundworm
- people get infected by ingesting infected feces (i.e. ingesting infected soil)
Toxoplasma gondii is most problematic for …
pregnant women - can cause birth defects
Trichomonas
-transmission
sexually transmitted
Parasitic infections associated with HIV in US
Pneumocystic jirovecii
Toxoplasma gondii
Cryptosporidium (assoc. w/ contaminated drinking water)
Parasitic infections associated with HIV globally
Malaria
Leishmania
Trypanosoma cruzi
What are the 5 types of human malaria?
Plasmodium falciparum Plasmodium vivax Plasmodium ovale Plasmodium malariae Plasmodium knowlesi
P. falciparum
responsible for most deaths
prodominant in tropics
infects all RBCs
P. vivax
relapsing malaria - caused by hypnozoites in liver - infects reticulocytes
common in subtropics and temerpate regions
P. ovale
relapsing malaria - caused by hypnozoites in liver
found in west Africa
Malaria life cycle
-sporozoites injected by mosquito - go to liver
- liver
- – merozoites formed
- – hypnozoites — vivax and ovale latent form causes relapse
- blood
- – merozoites invade & divide, rupture RBC, reinvade
- –sexual stages produce gametocytes
What can happen in terms of effects of malaria?
- cerebral malaria
- severe anemia
- metabolic acidosis
drugs that we have don’t treat these symptoms
Can we prevent malaria infection?
No, we don’t have drugs that kill sporozoites
What does it mean to be a tissue schizonticide? blood schizonticide?
tissue - acts on liver forms
blood - acts on RBC forms
What do gametocides do?
kill sexual stages & prevent transmission to mosquito
What drug works against both merozoites and hyp?
primaquine
What drugs are effective against merozites only?
atovaquone
artemisinins
Drugs that are effective against blood stages?
chloroquine mefloquine artemisinins quinine doxycyline & tetracycline clindamycin
What factors must be considered when treating someone for malaria?
- types of infecting parasite
- area where infection was required - this determines the resistance pattern
- clinical status of the patient
Artemisinin
- what important feature does it have?
- mechanism?
- Endoperoxide active group (required for the functioning of this drug)
- Mech not clear, but may involve toxic free radicals
- – active compound likely produced through interaction with intracellular iron
What is one of the big advantages of artemisinin?
what is the disadvantage?
It acts very quickly on the blood schizonticide
— 4 log reduction in parasite numbers in 48 hours
Short half-life
Artemisinin is active against … ?
What is it recommended for?
Active against all
Recommended for treatment of chloroquine-resistant P. falciparum
Artemisinin combination therapy
- what is it combined with?
- what is the idea behind this therapy?
- what is the down side?
combined with mefloquine or lumefantrine
idea is to combine it with something that has a long half life
artemisinin is better tolerated that most drugs so we don’t want to adversely affect patient with addition of another drug
How does artemisinin kill?
concentration dependent killing - meaning the higher the dose, the more effective the killing
What are the artemisinin derivates and how are they administered?
- artemisinin - oral
- artesunate - oral, IV, IM, rectal
- dihydroartemisinin - oral
- artemether - oral, IM, rectal
Artemisinin adverse effects
nausea, vomitting, diarrhea, dizziness
embryotoxic - not recommended in first trimester for uncomplicated malaria
How do 4-substituted quinolines work? Why does this work?
Resistance?
Interfere the polymerization of heme
Parasite ingests large amounts of Hg and degrade it. Free heme is toxic, so parasites polymerize it into hemozoin. The drugs prevent this pairing of heme molecules
R: Associated with lack of accumulation in food vacuole
Pharmacokinestics of chloroquine (generally)
- well absorbed
- very large Vd - slowly released from tissues
- initial half life of 3-5 days; terminal half life of 1-2 months
The effect of chloroquine is best seen with what kind of mechanisms of killing?
Time-dependent killing
note: this makes sense with the properties
What is the primary mechanism by which resistance was developed to chloroquine?
Mutations in PfCRT1
- localized to food vacuole
- causes reduce accumulation
Adverse effects of chloroquine
Adverse - Pruritus (esp Africans)
CONTRAINDICATIONS of chloroquine
Contraindications
- psoriasis or prophyria
- retina or visual field defects
- myopathy
Other chloroquine related compounds
- mefloquine
- lumefantine
- piperaquine
- amodiaquine
- halofantrine
- tafenoquine
Quinine and Quinidine act against?
Active against what others?
First line for what malaria?
Administration?
rapidly acting against blood schizonticide
active against Plasmodium and babesiosis
first line for falciparium
administration - oral for uncomplicated, IV for severe
What CYP are quinine and quinidine metabolized by?
CYP3A4
- can raise levels of warfarin and digoxin
- interacts with antiretroviral drugs
Adverse effects of quinine
Cinchonism
- tinnitus
- headache
- nausea
- dizziness
- flushing
- visual distrubances
Cardiotoxicity
Can stimulate uterine contractions
Hemolysis
- G6PD deficiency
- blackwater fever
Severe hypotension can occur from too-rapid infusion
MELFLOQUINE [Larium]
Used for what types of malaria?
Adverse effects?
erythrocytic forms - falciparum & vivax
used for both prophylaxis and rx
Adverse effects - neuropsychiatric toxicity
What things are seen with neuropsychiatric toxicity?
seizures
toxic psychosis
sleep disturbances
^recall, this is seen with MELFLOQUINE
Primaquine
Used for what stages?
Drugs of choice for liver stages of P. vivax and P. ovale
Its the only drug active against hyponozoites
It is gametocidal against all four malaria parasites
Primaquine contraindications?
Avoid in?
Contraindications
- G6PD deficiency
- –predisposes to hemolytic anemia
- –pregnancy - fetus is G6PD deficieny
Avoid in
- history of granulocytopenia or methmoglobinemia
- receiving potentially myelosuppressive drugs
- disorders that commonly include myelosuppression
Sulfadoxine targets …
DHPS (dihydropteroate synthase)
Pyrimethamine proguanil targets …
DHFR (dihydrofolate reductase)
Fansidar =
prymethamine-sulfadoxine
- folate synthesis inhibitors
- slow acting erythroctic schizonticide
Use of antifolates
-recommendation. why?
- use of single antifolates not recommended
- synergistic effect allows 20-fold reduction in dose of each component
- combo chosen because of matching pharmacokinetics (both have long half-lives)
Other uses of antifolates
- toxoplasmosis
- pneumocystis
(Pyrimethamine is 1000-fold selective for plasmodium)
Why is use of single antifolates not recommended?
resistance develops easily
Malarone is a combination of ..?
proguanil and atavaquone
What is atavaquone’s mechanism of action?
- disrupts mitochondrial electron transport
- failed when used alone due to rapidly developed resistance
What antibiotics have been showed to be effective as anti-malarials?
Why are these effective?
- tetracycline
- doxycycline
- clindamycin
(1-3 are blood schizonticides)
Parasite has a plant like organelle called apicoplasts - they carry out biochemical processes. These antibiotics target the organelle
