Antiparasitics: antiprotozal drugs

Question 1

Trypanosoma cruzi is also called ….

its transmitted by …

Answer 1

chagas disease

-rejuvid bug transmits it - bug defecates on skin and then later person itches the fecal matter into the skin

Question 2

Taenia solium, aka …

it causes …

Answer 2

pork tapeworm

-causes cysticercosis and neurocyticercosis

Question 3

Toxicara is typically a ____ infection

-its ____ ___ worm

Answer 3

zoonotic

• dog and cat roundworm
• people get infected by ingesting infected feces (i.e. ingesting infected soil)

Question 4

Toxoplasma gondii is most problematic for …

Answer 4

pregnant women - can cause birth defects

Question 5

Trichomonas

-transmission

Answer 5

sexually transmitted

Question 6

Parasitic infections associated with HIV in US

Answer 6

Pneumocystic jirovecii
Toxoplasma gondii
Cryptosporidium (assoc. w/ contaminated drinking water)

Question 7

Parasitic infections associated with HIV globally

Answer 7

Malaria
Leishmania
Trypanosoma cruzi

Question 8

What are the 5 types of human malaria?

Answer 8

Plasmodium falciparum
Plasmodium vivax
Plasmodium ovale
Plasmodium malariae
Plasmodium knowlesi

Question 9

P. falciparum

Answer 9

responsible for most deaths
prodominant in tropics
infects all RBCs

Question 10

P. vivax

Answer 10

relapsing malaria - caused by hypnozoites in liver - infects reticulocytes

common in subtropics and temerpate regions

Question 11

P. ovale

Answer 11

relapsing malaria - caused by hypnozoites in liver

found in west Africa

Question 12

Malaria life cycle

Answer 12

-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

Question 13

What can happen in terms of effects of malaria?

Answer 13

1. cerebral malaria
2. severe anemia
3. metabolic acidosis

drugs that we have don’t treat these symptoms

Question 14

Can we prevent malaria infection?

Answer 14

No, we don’t have drugs that kill sporozoites

Question 15

What does it mean to be a tissue schizonticide? blood schizonticide?

Answer 15

tissue - acts on liver forms

blood - acts on RBC forms

Question 16

What do gametocides do?

Answer 16

kill sexual stages & prevent transmission to mosquito

Question 17

What drug works against both merozoites and hyp?

Answer 17

primaquine

Question 18

What drugs are effective against merozites only?

Answer 18

atovaquone

artemisinins

Question 19

Drugs that are effective against blood stages?

Answer 19

chloroquine
mefloquine
artemisinins
quinine
doxycyline & tetracycline
clindamycin

Question 20

What factors must be considered when treating someone for malaria?

Answer 20

1. types of infecting parasite
2. area where infection was required - this determines the resistance pattern
3. clinical status of the patient

Question 21

Artemisinin

• what important feature does it have?
• mechanism?

Answer 21

• 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

Question 22

What is one of the big advantages of artemisinin?

what is the disadvantage?

Answer 22

It acts very quickly on the blood schizonticide
— 4 log reduction in parasite numbers in 48 hours

Short half-life

Question 23

Artemisinin is active against … ?

What is it recommended for?

Answer 23

Active against all

Recommended for treatment of chloroquine-resistant P. falciparum

Question 24

Artemisinin combination therapy

• what is it combined with?
• what is the idea behind this therapy?
• what is the down side?

Answer 24

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

Question 25

How does artemisinin kill?

Answer 25

concentration dependent killing - meaning the higher the dose, the more effective the killing

Question 26

What are the artemisinin derivates and how are they administered?

Answer 26

1. artemisinin - oral 2. artesunate - oral, IV, IM, rectal 3. dihydroartemisinin - oral 4. artemether - oral, IM, rectal

Question 27

Artemisinin adverse effects

Answer 27

nausea, vomitting, diarrhea, dizziness embryotoxic - not recommended in first trimester for uncomplicated malaria

Question 28

How do 4-substituted quinolines work? Why does this work? Resistance?

Answer 28

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

Question 29

Pharmacokinestics of chloroquine (generally)

Answer 29

1. well absorbed 2. very large Vd - slowly released from tissues 3. initial half life of 3-5 days; terminal half life of 1-2 months

Question 30

The effect of chloroquine is best seen with what kind of mechanisms of killing?

Answer 30

Time-dependent killing | note: this makes sense with the properties

Question 31

What is the primary mechanism by which resistance was developed to chloroquine?

Answer 31

Mutations in PfCRT1 - localized to food vacuole - causes reduce accumulation

Question 32

Adverse effects of chloroquine

Answer 32

Adverse - Pruritus (esp Africans)

Question 33

CONTRAINDICATIONS of chloroquine

Answer 33

Contraindications 1. psoriasis or prophyria 2. retina or visual field defects 3. myopathy

Question 34

Other chloroquine related compounds

Answer 34

1. mefloquine 2. lumefantine 3. piperaquine 4. amodiaquine 5. halofantrine 6. tafenoquine

Question 35

Quinine and Quinidine act against? Active against what others? First line for what malaria? Administration?

Answer 35

rapidly acting against blood schizonticide active against Plasmodium and babesiosis first line for falciparium administration - oral for uncomplicated, IV for severe

Question 36

What CYP are quinine and quinidine metabolized by?

Answer 36

CYP3A4 - can raise levels of warfarin and digoxin - interacts with antiretroviral drugs

Question 37

Adverse effects of quinine

Answer 37

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

Question 38

MELFLOQUINE [Larium] Used for what types of malaria? Adverse effects?

Answer 38

erythrocytic forms - falciparum & vivax used for both prophylaxis and rx Adverse effects - neuropsychiatric toxicity

Question 39

What things are seen with neuropsychiatric toxicity?

Answer 39

seizures toxic psychosis sleep disturbances ^recall, this is seen with MELFLOQUINE

Question 40

Primaquine Used for what stages?

Answer 40

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

Question 41

Primaquine contraindications? Avoid in?

Answer 41

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

Question 42

Sulfadoxine targets ...

Answer 42

DHPS (dihydropteroate synthase)

Question 43

Pyrimethamine proguanil targets ...

Answer 43

DHFR (dihydrofolate reductase)

Question 44

Fansidar =

Answer 44

prymethamine-sulfadoxine - folate synthesis inhibitors - slow acting erythroctic schizonticide

Question 45

Use of antifolates | -recommendation. why?

Answer 45

- 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)

Question 46

Other uses of antifolates

Answer 46

1. toxoplasmosis 2. pneumocystis (Pyrimethamine is 1000-fold selective for plasmodium)

Question 47

Why is use of single antifolates not recommended?

Answer 47

resistance develops easily

Question 48

Malarone is a combination of ..?

Answer 48

proguanil and atavaquone

Question 49

What is atavaquone's mechanism of action?

Answer 49

- disrupts mitochondrial electron transport | - failed when used alone due to rapidly developed resistance

Question 50

What antibiotics have been showed to be effective as anti-malarials? Why are these effective?

Answer 50

1. tetracycline 2. doxycycline 3. clindamycin (1-3 are blood schizonticides) Parasite has a plant like organelle called apicoplasts - they carry out biochemical processes. These antibiotics target the organelle