Exam 3: Antimalarial Drugs Flashcards
What is the DOC for Malaria that does not have any drug resistance?
Chloroquine
What genus does Protozoa belong to?
Plasmodia
What are the 4 Protozoa species that cause malaria in humans?
- P. Falciparum
- P. Vivax
- P. Ovale
- P. Malariae
What are the two types of malaria protozoa that are dormant and stay in the liver?
P. Vivax and P. Ovale
What is the most lethal form of malaria?
P. Falciparum
What symptoms does P. Falciparum malaria cause?
- Fever every 3rd day
- Severe blood loss anemia
- Cerebral malaria (clogs vessels in the brain)
What is the most common form of malaria?
P. Vivax
What are the malaria species called when they are dormant in the liver?
Hyponozoites
What symptoms does malaria caused by P. Vivax cause?
- Chills and fever every 3rd day
- Relapses months to years after mosquito bite due to dormant forms
What is the most rare form of malaria?
P. Ovale
What are the two types of malaria that cause relapses and why?
P. Ovale and P. Vivax because they have dormant stages in the liver and can be reactivated at any time
What symptoms does malaria caused by P. Malaria have?
- Fever every 4th day
- Chronic infection that can last a lifetime
What is a clinical cure for malaria?
Erythrocytes forms of the parasite have been eradicated and the patient is symptom free (Dormant Protozoa in the liver do no get eradicated)
What is a radical cure for malaria?
All forms of the parasite, including any secondary tissue forms have been eradicated.
-Infections by P. Vivax and P. Ovale need radical cures
What do blood schizonticides do?
They act on erythrocytes forms of the malaria parasite and can be used to suppress symptoms and provide a so-called “clinical cure”
-Does NOT affect secondary tissue forms of P. Vivax or P. Ovale
What do tissue schizonticides do?
Eliminate the Protozoa from the tissue (acts on the dormant hepatic stages)
- Does not suppress symptoms once erythrocytes stages have been established
- Prevents relapse
If you have a patient with a dormant form of malaria, how should you treat them?
A blood and a tissue schizonticide
What are the recommended treatments for uncomplicated malaria with a chloroquine resistance?
Artesunate + Atovoquone/proguanil
OR
Artemether-lumefantrine
“ACT” drugs
How does malaria form resistance against Chloroquine?
Transport pumps
What is the MOA of Chloroquine?
Interferes with lysosomal degradation of hemoglobin
How is chloroquine absorbed and what inhibits its absorption?
Taken orally, absorbed in the GI tract.
-Mg+ and Ca+ antacids inhibit absorption
Where does chloroquine accumulate once absorbed? What can this cause?
Melanin-rich tissues, like the skin and retina.
This can cause retinal and cornea toxicity and is contraindicated in patients with ocular disease
How is chloroquine metabolized?
In the liver by a substrate of CYP34A
What are the toxicities associated with chloroquine?
Retinal and corneal toxicity, hemolysis (G6PD patients), and QT prolongation
What are the contraindications of Chloroquine?
Patients with ocular disease, psoriasis, and porphyria
What drugs have the fastest action against P. Falciparum?
The artemisinin - artesunate and artemether
**They do have a short half life and are always combined with other antimalarial drugs
What type of drugs are Proguanil and pyrimethamine + sulfadoxine?
What type of malaria do they attack?
Folate metabolism inhibitors
Main effect on erythrocytic forms
How does resistance develop against the folate metabolism inhibitors?
Mutations in Dihydrofolate reductase
What is the MOA of the folate metabolism inhibitors?
Suldadoxine inhibits the incorporation of PABA into the folic acid.
Pyrimethamine and proguanil inhibit dihydrofolate reductase, blocking conversion of dihydrofolate reductase into tetrahydrofolic acid
What antimalarials are often used in conjunction with artemisinins?
Atovoquone, lumefantrine, mefloquine, and sulfadoxine-pyrimethamine
What is the MOA of Atovoquone + Proguanil?
- Atovoquone interferes with mitochondrial electron transport, ATP, and pyrimidine biosynthesis
- Proguanil- Prodrug that is converted to cycloguanil, inhibits dihydrofolate reductase
Together, they are synergistic
What is Atovoquone + Proguanil often combined with and why?
Artesunate for rapid clearance and decrease in resistance
What are the side effects of Atovoquone + Proguanil that require discontinuation of the drug?
Rash, fever, vomiting, diarrhea
*caution with pregnancy, caused mutations in mouse tests
What is lumefantrine used in combination with?
Artemether
What are the toxicities associated with lumefantrine?
Headache (56%) and QT prolongation
What kind of malaria does Quinine and Quinidine gluconate treat?
Complicated, chloroquine resistance plasmodia
What is Quinine and Quinidine Gluconate often combined with and why?
Doxycycline, tetracycline, or Clindamycin because it reduces the length of the treatment and therefore the adverse side effects are reduced
What is important to remember about the dosing for Quinine?
It have a very narrow margin between effective dose and toxic dose
What are the toxicities associated with quinine and quinidine Gluconate?
- Cinchonism: Tinnitus, headache, dizziness, flushing, visual disturbance
- Anti-arrhythmic agent
- Hemolysis in G6PD deficient patients
- QT prolongation
- Diarrhea
What form of malaria do antibiotics help treat?
Complicated, chloroquine-resistance malaria (quinine and Clindamycin in children/pregnant women)
What form of malaria does Mefloquine act on?
Erythrocytic forms, however resistance and toxicity limits use (drug of last resort)
How is Mefloquine metabolized?
Absorbed in the GI tract with a bioavailability greater than 85%, metabolized in the liver, and eliminated very slowly via bile in the feces (permits single dose regimen)
What are the toxicities associated with Mefloquine?
Depression of the myocardium (do NOT combine with quinine!)
Seizures
Latent psychosis
Vivid dreams
When is mefloquine not recommended?
Should not be used in patients with mental illness or epilepsy
Not recommended in pregnancy due to teratogenicity
When is pyrimethamine + sulfadoxine used for malaria tx?
Empirical treatment and preventative intermittent therapy in pregnant women
What type of drug is Primaquine?
Tissue schizonticide- only active against tissue forms.
What are the contraindications of Primaquine?
SLE or RA (granulocytopenia)
*not recommended in pregnancy, infancy, breastfeeding due to fatal hemolytic anemia (G6PD status of baby is unknown)
What is the major toxicity associated with Primaquine?
Hemolytic anemia in G6PD patients
What type of drug is Tafenoquine?
Tissue schizonticide against against ALL stages of disease
What are the contraindications of Tafenoquine?
G6PD deficiency or G6PD status is unknown
What are the uses of Tafenoquine in malaria tx?
Used as a radical cure and terminal prophylaxis
What is Cinchonism and what drug is it associated with?
Tinnitus, headache, dizziness, flushing, visual disturbance
-Quinine/Quinidine
