Antimalarials Flashcards
What are the four species of plasmodium that typically cause human malaria?
Plasmodium Falciparum, vivax, malariae, ovale
What is the parasite life cycle of malaria?
- Anopheline Mosquito inoculates plasmodium sporozoites to initiate human infection
- Circulating sporozoites rapidly invade liver cells
- Exoerythrocytic stage tissue schizonts mature in the liver
- Merozoites are released from the liver and invade erythrocytes
- Gametocytes develop in erythrocytes before being taken up by mosquitos and completing the cycle.
For P. falciparum and P. malariae, what are some specific aspects?
Only one cycle of liver invasion
Liver infections ceases in less than 4 weeks
Only erythrocytic parasites have to be eliminated
For P. vivax and P. ovale, what are some specific aspects?
Have a dormant hepatic stage
Erythrocytic and hepatic parasites have to be eliminated
What is the incubation period for each species of Plasmodium?
P. vivax: 2 to 17 days
P. falciparum: 9 to 14 days
P. ovale: 16 to 18 days
P. malariae: 18 to 40 days (can be years)
What are the symptoms of malaria?
Malarial paroxysm (fever, anemia, jaundice, splenomegaly, hepatomegaly) In established infections, malarial paroxysms typically occur about every 2-3 days
What are some features of P. Falciparum?
Most severe disease (microvascular effects)
Only species likely to cause fatal disease if untreated
Cerebral malaria (irritability —- seizures — coma)
Symptoms: respiratory distress syndrome, diarrhea, severe thrombocytopenia, spontaneous abortion, hypoglycemia
Can cause rapidly progressive severe illness or death
What is prophylaxis for malaria?
Prevention of mosquito bites:
insect repellents
insecticides
bed nets
Treatment of malaria should be guided by 3 main factors
- Infecting Plasmodium Species
- Clinical status of patients
- Drug susceptibility of the infecting parasites
What are features of infecting plasmodium species?
P. vivax and P. ovale: infections require treatment for the hypnozoite forms dormant in the liver
P. falciparum and P. vivax: have different resistance patterns in different geographic areas
How do you treat uncomplicated vs complicated malaria?
Uncomplicated: tx with oral antimalarials
Complicated: treat aggressively with parenteral antimalarials
Moving onto the drugs, the first drug used is Chloroquine. What are some features?
Clinical application:
- -DOC in tx of non falciparum and sensitive uncomplicated falciparum malaria
- -preferred chemoprophylatic agent in areas without resistant falciparum malaria
What is the antimalarial action and MOA of chloroquine?
Antimalarial Action:
–highly effective against blood parasites
–not active against liver stage parasites
MOA:
–concentrates in parasite food vacuoles
–prevents biocrystallization of hemoglobin breakdown product heme to non heme hemozin
look at pic in powerpoint
What are the PK, Resistance for Chloroquine?
PK:
–oral and half life is 3-5 days (only need to take once weekly)
Resistance:
P. falciparum: mutations in putative transporter, PfCRT are common
What are the AE and Contraindications of Chloroquine?
AE:
–Generally well tolerated (At therapeutic doses)
—Pruritus (common in Africans)
–hemolysis in G6PD deficient people
–can cause electrocardiographic changes
Contraindications:
–psoriasis or porphyria (may precipitate attacks)
–retinal or visual field abnormalities
Safe in kids and pregos
Next drugs for Malaria are Quinine and Quinidine. What are some feature?
First line therapy for severe falciparum disease
Quinidine (Stereoisomer of quinine)
Clinical applications:
–parental treatment of severe falciparum malaria (quinidine)
–oral treatment of falciparum malaria (alternative in chloroquine resistant areas) (quinine)
What is the antimalarial action and MOA of Quinine and Quinidine?
Antimalarial Action:
–rapidly acting, highly effective against blood parasites
–not active against liver stage parasites
MOA:
–depressed O2 uptake and carbohydrate metabolism
-intercalates into DNA, disrupting parasites replication and transcription
What are the PK and Resistance of Quinine and Quinidine?
PK
–Quinine: oral tx of uncomplicated malaria
–Quinidine: IV tx for severe malaria
Resistance:
–likely to be an increasing problem and already common in some areas of south east asia
What are AE for Quinine and Quinidine?
AE:
- -Cinchonism: tinnitus, headache, dizziness
- -Hypersensitivity: skin rashes, urticaria, angioedema
- -Hematologic abnormalities: hemolysis, leukopenia
- -Hypoglycemia: stimulation of insulin release
- -Uterine contractions: still used in tx of severe falciparum malaria in pregos
- -Severe hypotension: too rapid IV infusion
- -ECG abnormalities: QT prolongation
- -Blackwater fever: hemolysis and hemoglobinuria
What are the contraindications for Quinine and Quinidine?
Discontinue if signs of:
severe cinchonism, hemolysis, and hypersensitivity
Avoid if possible in patients with:
–visual or auditory problems
Use with caution in patients with:
–underlying cardiac abnormalities
Do not use concurrently with mefloquine
Can rise plasma levels of warfarin and digoxin
Reduce dose in renal insufficiency
Pregnancy: cat C benefits do often outweigh risks in complicated malaria
The next malaria drug is Mefloquine. What are some features?
Effective against many chloroquine-resistant strains
Chemically related to quinine
MOA:
–destruction of the asexual blood forms of malarial pathogens
What are the clinical applications of Mefloquine?
Chemoprophylaxis: effective against most strains of P. falciparum and P. vivax
–currently only medication recommended for chemoprophylaxis in pregnant women in chloroquine resistant areas
Tx: can be used to tx mild to moderate acute malaria caused by P. falciparum and P. vivax
Mefloquine + artesunate: used in tx of uncomplicated malaria in regions of SE Asia
What are the PK and Resistance of Mefloquine?
PK
–oral only and elimination is 20 days so weekly prophylatic dosing
Resistance:
–uncommon
What are the AE and contraindications for Mefloquine?
AE:
–serious neurological and psychiatric toxicities: dizziness and loss of balance and hallucinations
–weekly dosing: sleep and behavioral disturbances
–higher treatment doses: leukocytosis and thrombocytopenia, aminotransferases elevations
Contraindications:
–patients with a history of: epilepsy, psychiatric disorders, arrhythmia, cardiac conduction defects
–Do Not coadminister with quinine, quinidine or halofantrine
–considered safe in young children and pregnancy
The next antimalarial drug is Primaquine. What are some features?
Drug of choice for eradication of dormant liver forms of P. vivax and P. ovale
Clinical Applications:
—therapy of acute vivax and ovale malaria
—terminal prophylaxis of vivax and ovale malaria
–chemoprophylaxis: protection against falciparum and vivax (Toxicities are a concern)
What is the antimalarial action and MOA of Primaquine?
Antimalarial Action:
—only available agent active against dormant liver forms of P. vivax and P. ovale
MOA:
–not understood
What is the PK and resistance of Primaquine?
PK:
–oral
–metabolites have less antimalarial activity but more potential for inducing hemolysis
Resistance:
–resistant strains may require therapy to be repeated and dose to be increased
What are the AE and contraindications for Primaquine?
AE:
Generally well tolerated
Infrequent (nausea, epigastric pain, headache)
Rare (leukopenia, agranulocytosis, leukocytosis0
Hemolysis or methemoglobinemia (Esp in G6PD patients)
Contraindications:
–G6PD deficiency
—pregnancy: fetus is relatively G6PD deficient (FDA category not yet assigned). do not use during pregnancy
Explain the relationship between Primaquine and G6PD deficiency.
G6PD deficiency results in a decrease in NADPH and GSH synthesis, making the cell more sensitive to oxidative agents. This causes hemolysis
Primaquine oxidizes GSH to GSSG. Therefore, less GSH is available to neutralize toxic compounds
pic on slide 43
Patients should be tested for G6PD deficiency before primaquine is prescribed
For severely G6PD deficient patients withhold therapy and tx relapses
The next antimalarial drug is Malarone, what are some features?
Malarone = atovaquone + proguanil
Clinical applications:
–tx and prophylaxis of P. falciparum
Antimalarial action:
–active against tissue and erythrocytic schizonts
—chemoprophylaxis can be started 1-2 days before travel and discontinued 1 week after exposure
What is the MOA, PK and AE for Malarone?
MOA: --disrupts mitochondrial electron transport PK ---oral only Adverse effects: --generally well tolerated --do not use in pregnancy
