Antimalarials Flashcards
Which species cause the most cases of malaria?
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. *
Drug List: Artemisinins
Artemisinins - BLOOD STAGE
- **Artemether
- Artesunate
- ACT with Lumefantrine**
Drug List: Quinolines
Quinolines & related compounds - BLOOD STAGE
- *- Quinine sulfate
- Chloroquine
- Primaquine **primary and hypnozoite liver stages**, gametocyte blood stage
Drug list: adjunctives with quinolines
- *- Doxycycline
- Clindamycin
- Tetracycline**
- *- Atovaqone/proguanil (**primary liver and blood stages)**
Malaria Lifecycle
Drug Therapy principles
may require > 1 drug!!!!
not used: pyrimethamine, sulfadoxine
useful: atovaquone/proguanil and primaquine good for liver stages
Where do you get artesunate?
Have to get through the CDC
Main MOA of antimalarials
- Interfere with DNA/RNA synthesis
- Inhibit ETC
- oxidative stress
- inhibit heme degradation
Artemisinin Use
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
Artemisinin administration
Oral/IM (artemether); IV/rectal (artesunate)
Best treatment guidlines: Artemisinins
Not useful for prophylaxis due to short 1/2 life
failure as monotherapy, ACT = combo therapy!!
Proposed MOA of Artemisinin
Toxic adduct? peroxide bridge potentially reduced by heme
Artemesinin-based Combination Therapies (ACT)
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
Artemisin Adverse Effects
Generally well tolerated, not recommended for children < 5kg or during **1st trimester of pregnancy **
CDC Guidelines for the Use of Artesunate
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
Quinolines & Related Compounds: Quinine
Mainstay for chloroquine-R and MDR P. falciparum asexual blood stages; gametocyticidal against P.vivax & P.ovale
**Interferes with heme digestion
Quinine Administration
Oral, IM (IV quinidine enantiomer-more potent/toxic)
NOTE: Resistance reported SE Asia, SA - Pfmdr1 gene amplification
Quinine Adverse Effects
Fatal oral dose (adults) = 2-8 g
Cinchonism: tinnitus, deafness, visual disturbance, headache, nausea, vomiting, dizziness, flushing
When do you have increased hemolysis with quinine toxicity?
G6PD deficiency
What are **more severe **quinine adverse effects?
Hypoglycemia-stimulates insulin release
Hypotension rare but serious (IV)
Cardiotoxicity with OD (quinidine more toxic)
Quinine Contraindications
Caution in patients w/ hypersensitivity
\*\*Discontinue if evidence of hemolysis
Contraindicated in patients with tinnitus/optic neuritis
Caution in patients with **cardiac dysrhythmias **
Is quinine safe in pregnancy?
potentially. must monitor glucose
Quinine Drug interations
Aluminum-containing antacids delay GI absorption
**INCREASE **plasma warfarin and digoxin levels
**DECREASE **DOSE w/renal insufficiency
Adjunctive Therapies with Quinine/Quinidine
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 _
