Antimalarials

Question 1

Which species cause the most cases of malaria?

Answer 1

P. vivax (subtropical)

P. falciparum (tropical, medical emergency! esp. pg and children)

*1 million deaths/year (infants & young children)
90% of the worlds deaths to Malaria occur in sub-Saharan Africa. *

Question 2

Drug List: Artemisinins

Answer 2

Artemisinins - BLOOD STAGE

• **Artemether
• Artesunate
• ACT with Lumefantrine**

Question 3

Drug List: Quinolines

Answer 3

Quinolines & related compounds - BLOOD STAGE

• *- Quinine sulfate
• Chloroquine
• Primaquine **primary and hypnozoite liver stages**, gametocyte blood stage

Question 4

Drug list: adjunctives with quinolines

Answer 4

• *- Doxycycline
• Clindamycin
• Tetracycline**
• *- Atovaqone/proguanil (**primary liver and blood stages)**

Question 5

Malaria Lifecycle

Answer 5

Question 6

Drug Therapy principles

Answer 6

may require > 1 drug!!!!

not used: pyrimethamine, sulfadoxine

useful: atovaquone/proguanil and primaquine good for liver stages

Question 7

Where do you get artesunate?

Answer 7

Have to get through the CDC

Question 8

Main MOA of antimalarials

Answer 8

1. Interfere with DNA/RNA synthesis
2. Inhibit ETC
3. oxidative stress
4. inhibit heme degradation

Question 9

Artemisinin Use

Answer 9

Ancient Chinese herbal remedy (qing hao; sweet wormwood)

P. falciparum and asexual blood stages of P. vivax; gametocytocidal action

Anti-malarial activity has been attributed to endoperoxide moiety.

*** Induce their own CYP2B6 and 3A4-mediated metabolism

Question 10

Artemisinin administration

Answer 10

Oral/IM (artemether); IV/rectal (artesunate)

Question 11

Best treatment guidlines: Artemisinins

Answer 11

Not useful for prophylaxis due to short 1/2 life

failure as monotherapy, ACT = combo therapy!!

Question 12

Proposed MOA of Artemisinin

Answer 12

Toxic adduct? peroxide bridge potentially reduced by heme

Question 13

Artemesinin-based Combination Therapies (ACT)

Answer 13

Partner w/ drugs with longer t1/2
** WHO-recommended 1st line Tx for chloroquine-R P. falciparum

Artemether-Lumefantrine (Coartem) - blood schizonticides

Substantial drug-drug interactions with antiretrovirals/protease inhibitors (may need to increase ACT dose) • absorption increased when taken with high fat meal

Question 14

Artemisin Adverse Effects

Answer 14

Generally well tolerated, not recommended for children < 5kg or during **1st trimester of pregnancy **

Question 15

CDC Guidelines for the Use of Artesunate

Answer 15

severe malaria disease
high levels of malaria parasites in the blood
inability to take oral medications
lack of timely access to intravenous quinidine quinidine intolerance or contraindications quinidine failure

Question 16

Quinolines & Related Compounds: Quinine

Answer 16

Mainstay for chloroquine-R and MDR P. falciparum asexual blood stages; gametocyticidal against P.vivax & P.ovale

**Interferes with heme digestion

Question 17

Quinine Administration

Answer 17

Oral, IM (IV quinidine enantiomer-more potent/toxic)

NOTE: Resistance reported SE Asia, SA - Pfmdr1 gene amplification

Question 18

Quinine Adverse Effects

Answer 18

Fatal oral dose (adults) = 2-8 g

Cinchonism: tinnitus, deafness, visual disturbance, headache, nausea, vomiting, dizziness, flushing

Question 19

When do you have increased hemolysis with quinine toxicity?

Answer 19

G6PD deficiency

Question 20

What are **more severe **quinine adverse effects?

Answer 20

Hypoglycemia-stimulates insulin release

Hypotension rare but serious (IV)

Cardiotoxicity with OD (quinidine more toxic)

Question 21

Quinine Contraindications

Answer 21

Caution in patients w/ hypersensitivity

  \*\*Discontinue if evidence of hemolysis

Contraindicated in patients with tinnitus/optic neuritis

Caution in patients with **cardiac dysrhythmias **

Question 22

Is quinine safe in pregnancy?

Answer 22

potentially. must monitor glucose

Question 23

Quinine Drug interations

Answer 23

Aluminum-containing antacids delay GI absorption

**INCREASE **plasma warfarin and digoxin levels

**DECREASE **DOSE w/renal insufficiency

Question 24

Adjunctive Therapies with Quinine/Quinidine

Answer 24

Doxycycline, tetracycline and clindamycin (blood schizonticides)

• *- Ineffective monotherapy**
• Useful as an adjunct to treat P. falciparum

Inhibit protein translation in protozoa-result in _death of progeny _