Antiparasites

Question 1

Major killers from parasitic infections

Answer 1

1. Malaria
2. Schisto
3. Trypanosomiasis

Question 2

Why do most of these drugs get selectively concentrated into the parasite?

Answer 2

This is due to GI absorption and location of the parasites

Question 3

Nitroimidazoles

Answer 3

• pro-drug targets an enzyme that is unique to the parasite
• causes oxidative damage to the parasite due to free radical.
• Safe in humans because of aerobic respiration regenerating the parent drug
• Renal excretion
• Target : anaerobes

Question 4

You have a pt that comes in with severe diarrhea and fatty stools after traveling and having ice in their drink. What do you treat them with?

Answer 4

Metronidazole because they have giardiasis.

Question 5

What does metronidazole taste like?

Answer 5

Like chewing a battery… so metallic and nasty.

Question 6

Adverse reactions / contraindications of metronidazole

Answer 6

• HA and Nausea
• Peripheral neuropathy
• 1st trimester preg
• Liver disease
• Renal dysfunction

Question 7

Drug interactions of metronidazole

Answer 7

• Alcohol induces disulfiram like state (n/v)
• Disulfiram
• Inducers of hepatic enzymes

Question 8

Paromomycin

Answer 8

Aminoglycoside antibiotic
MOA: binds to A-site of ribosomes to inhibit protein synthesis
- Low absorption so concentrated in parasite in gut.

Question 9

What do you treat with paromomycin

Answer 9

• Amebiasis
• Leishmanias
• Cryptosporidiosis

Question 10

Treatment of toxo

Answer 10

Pyrimethamine _ sulfadiazine or if sulfa allergy go for clindamycin

• antifolate combinations that selectively target parasite enzymes

Question 11

Where do sulfonamides inhibit?

Answer 11

PABA + pteridine —X—> Dihydropteroic acid

Question 12

Where does pyrimethamine inhibit?

Answer 12

@ DHFR

Question 13

Pentamidine treats..?

Answer 13

Used mostly for P. carinii for PCP, alternative to TMP-SMX

West african Trypanosomiasis

Visceral Leishmanias

Question 14

How does pentamidine work

Answer 14

Inhibit SAM decarboxylase to disrupt polyamine biosynthesis

Bind minor groove of DNA to inhibit protein synthesis

Inhibit type II topoisomerase

Interferes with glucose metabolism

Question 15

Drug interactions of pentamidine

Answer 15

Methotrexate - DHFR inhibitor

Question 16

Which route of administration of pentamidine is used today, and how is it tolerated?

Answer 16

Inhalation and it is well tolerated with few side effects

Question 17

Benzimidazoles treat what…?

Answer 17

Nematode infections

Focus on mebendazole and albendazole because thiabendazole has lots of side effects.

Question 18

MOA of Benzimidazoles

Answer 18

Inhibit microtubule formation by binding the beta-tubulin to prevent formation of alpha/beta dimers

Selectively binds to parasite tubulin (100x fold selectivity over human)

Question 19

What causes the selectivity for benzimidazoles?

Answer 19

Humans have a point mutation: Phe200–>Tyr which introduces an -OH group that the drug won’t pick.

Question 20

Mebendazole

Answer 20

• Poor absorption so good concentration in parasite
• 95% bound to plasma protein
• Metabolism to inactive products
• Bile elimination
• Use in uncomplicated nematode infections

Question 21

Albendazole

Answer 21

• Better absorption
• Systemic distribution
• Metabolism to sulfoxide required for activity
• Renal elim
• Use for cysticercosis

Question 22

Are the benzimidazoles safe in pregnancy?

Answer 22

No! Not safe in pregnancy of

Question 23

You have someone with symptomatic epilepsy presenting to your clinic and you suspect cysticercosis. What do you treat with?

Answer 23

Albendazole

Question 24

Pyrantel Pamoate

Answer 24

Use for roundworm, hookworm, and pinworm infections

• concentrates in parasite
• MOA = ACh receptor agonist = spastic paralysis of worm

Contraindications:
- liver dysfunction

DDI:
- Piperazine - Ach receptor antagonist

Question 25

Praziquantel

Answer 25

Use for tapeworm and flukes besides cysticercosis MOA: Ca2+ ionophore - induces tegmental damage and activates the immune system. induces paralysis, detachment and excretion

Question 26

When do you avoid praziquantel?

Answer 26

- if there is a risk of neurocysticercosis because it can cause permanent damage - Don't use in pregnancy

Question 27

What treats leishmania?

Answer 27

Sodium stibogluconate

Question 28

Treatment goals of malaria infection

Answer 28

1. Prophylaxis to prevent infection 2. Treat acute febrile stage of infection 3. Eradicate latent forms

Question 29

Chloroquine

Answer 29

- Used to treat erythrocytic stage of malaria - More potent and less toxic than quinine - Anti-cancer drug targeting autophagy

Question 30

MOA of Chlorquine

Answer 30

- Concentrates in food vacuoles - Inhibits heme polymerization - inhibits peroxidase and catalase activity - generates oxidative stress

Question 31

What does failure to respond to chloroquine mean?

Answer 31

Resistant infection

Question 32

Adverse reactions to chloroquine

Answer 32

- transiently high dose - CV effects - CNS dysfunction (coma, confusion, convulsion) Symptoms of cinchonism

Question 33

Quinine

Answer 33

- treatment of MDR malaria | - Used as a combo drug with lots of Abx

Question 34

MOA of quinine

Answer 34

- Inhibits parasite feeding mechanism - Generates oxidative stress Resistance: - Increased levels of PfMDR protein Pgh-1

Question 35

Cinchonism

Answer 35

- Visual impairments - Auditory tinnitus - GI n/v rashes

Question 36

Pharmacokinetics of quinine

Answer 36

- during febrile stages it binds an a-1-acid glycoprotein which lowers bioavailability and decreases the half life. - during afebrile stages get higher availability and lower half life. If not responding to drug early on, try to lower dose so that you don't have side effects. If loading dose is IV, switch to oral as soon as possible

Question 37

DDIs of Quinine

Answer 37

May raise plasma levels of anticoagulants and cardiac glycosides

Question 38

Adverse reactions of quinine

Answer 38

- Cinchonism - Stimulates pancreatic beta-cells - Hypotension - Hemolysis in G6PD deficiency

Question 39

Mefloquine

Answer 39

- Alternative treatment of erythrocytic stages of chloroquine resistant malaria - Prophylaxis during pregnancy - Causes a lot of psychotic disturbances

Question 40

MOA of mefloquine

Answer 40

- same as chloroquine (oxidative stress)

Question 41

Adverse reactions of mefloquine

Answer 41

- safe drug if you don't get the psychoses

Question 42

Malarone

Answer 42

- combo drug (atovaquone + proguanil) | - used for P. falciparum malaria, PCP, and toxo

Question 43

Adverse effects of malarone

Answer 43

Rash - history of skin reactions

Question 44

DDIs of malarone

Answer 44

Rifampin -used to treat pulmonary infection to reduce plasma levels

Question 45

MOA of malarone

Answer 45

DHFR inhibitor | Increases the efficacy of atovaquone to collapse protein gradient

Question 46

Contraindications to malarone

Answer 46

Don't give to kidney disease people.

Question 47

Primaquine

Answer 47

- ONLY drug to treat latent forms of malaria - Use in combo with blood schizonticide (chloroquine) - Gametocidal activity Reserve this for latent because it's the only one we have and you don't want resistance to develop!

Question 48

Artemisinin

Answer 48

- The drug of choice for MDR malaria in endemic areas | - Use in combo with chloroquine

Question 49

MOA of artemisinin

Answer 49

- interacts with heme and prevents heme polymerization

Question 50

What problems did we have with using artemisinin

Answer 50

- Requires 6 day treatment.. hard to get people to do | - Quick resistance developed in SE Asia

Question 51

MOA of primaquine

Answer 51

- Inhibit electron transport chains.

Question 52

Adverse reactions to primaquine

Answer 52

- GCPD deficiency leads to hemolytic anemia and can be life threatening!! ALWAYS TEST!