Antimalarials Flashcards
1
Q
Malarial paroxysm
A
- fever, anemia, jaundice, splenomegaly, hepatomegaly
- In established infections, malarial paroxysms typically occur about every 2-3 days
2
Q
P. falciparum sx
A
- Most severe disease (microvascular effects)
- Only species likely to cause fatal disease if untreated
- Cerebral malaria (irritability -> seizures -> coma)
- Symptoms: eg, respiratory distress syndrome, diarrhea, severe thrombocytopenia, spontaneous abortion,hypoglycemia
3
Q
Major antimalarials
A
- Chloroquine
- Quinine and Quinidine
- Mefloquine
- Primaquine
- Atovaquone
- Sulfadoxine-pyrimethamine
- Doxycycline
- Artemisinins
4
Q
Antimalarials according to clinical status of Pt
A
Uncomplicated: Treat with oral antimalarials
Complicated
- One or more of following: impaired consciousness /coma, severe normocytic anemia, renal failure, pulmonary edema, acute respiratory distress syndrome, circulatory shock, disseminated intravascular coagulation, spontaneous bleeding, acidosis, hemoglobinuria, repeated generalized convulsions, and/or parasitemia of >5%)
- Treat aggressively with parenteral antimalarials: Doxycycline
5
Q
Chloroquine
A
- DOC for both treatment & prophylaxis of all P. vivax and P. ovale malaria infections
- Use severely compromised by drug resistance
Clinical applications
- DOC in the treatment of non-falciparum and sensitive uncomplicated falciparum malaria
- **Preferred chemoprophylactic agent in areas without resistant falciparum malaria **
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-toxic hemozoin; prevents polymerization of heme to hemezoin
PK
- Oral
- t1/2 = 3-5 days (only need to take once weekly)
**Resistance: **P. falciparum: mutations in putative transporter, PfCRT are common
6
Q
Chloroquine - Adverse
A
- Generally well tolerated (at therapeutic doses)
- Pruritus (common in Africans)
- Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision, urticaria (uncommon)
- Hemolysis (G6PD-deficient people)
- Can cause electrocardiographic changes
Contraindications
- psoriasis or porphyria (may precipitate attacks)
- retinal or visual field abnormalities
- SAFE IN PREGNANCY & YOUNG CHILDREN
7
Q
Quinine and Quinidine
A
- Derived from cinchona tree bark
- First-line therapies for severe falciparum disease
- Resistance is uncommon but increasing
- Quinidine (stereoisomer of quinine)
Clinical Applications
- Parenteral treatment of severe falciparum malaria (Quinidine)
- Oral treatment of falciparum malaria (alternative in chloroquine-resistant areas) (Quinine)
Antimalarial Action
• Rapidly-acting, highly effective against blood parasites • NOT active against liver stage parasites
MOA
- Depresses O2 uptake and carbohydrate metabolism
- Intercalates into DNA, disrupting parasite’s replication and transcription
Pharmacokinetics
- Quinine: oral treatment of uncomplicated malaria
- Quinidine: IV treatment for severe malaria
Resistance
- Likely to be increasing problem
- Already common in some areas of South-east Asia
8
Q
Quinine & Quinidine - Adverse
A
- Cinchonism: tinnitus, headache, nausea, dizziness, flushing & visual disturbances
- Hypersensitivity: skin rashes, urticaria, angioedema, bronchospasm
- Hematologic abnormalities: hemolysis (G6PD deficiency), leukopenia, agranulocytosis, thrombocytopenia
- Hypoglycemia: stimulation of insulin release
- Uterine contractions: still used in treatment of severe falciparum malaria in pregnancy
- Severe hypotension: too rapid IV infusion
- ECG abnormalities: QT prolongation
- Blackwater fever: hemolysis & hemoglobinuria (likely hypersensitivity reaction)
Contraindications
- Discontinue if signs of:
- severe cinchonism
- hemolysis
- 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 raise plasma levels of warfarin & digoxin • Reduce dose in renal insufficiency
- Pregnancy: FDA Category C (however benefits do often outweigh risks in complicated malaria)
9
Q
Mefloquine
A
- Effective against many chloroquine-resistant strains
- Chemically related to quinine
- MOA: Destruction of the asexual blood forms of malarial pathogens. Details unknown.
Clinical applications
- Chemoprophylaxis: effective against most strains of P. falciparum and P.vivax
- Currently only medication recommended for chemoprophylaxis in pregnant women in chloroquine-resistant areas
- Treatment : can be used to treat mild to moderate acute malaria caused by P.falciparum and P.vivax
- Mefloquine + artesunate used in treatment of uncomplicated malaria in regions of Southeast Asia
Pharmacokinetics
• Oral only
• Elimination t1/2 = 20 days (weekly prophylactic dosing)
Resistance
- Uncommon but has been reported
- Associated with resistance to quinine but not chloroquine
10
Q
Mefloquine - Adverse
A
- Serious neurological and psychiatric toxicities: Dizziness, loss of balance, ringing in the ears, anxiety, depression, hallucinations
- Weekly dosing: Nausea, vomiting, diarrhea, dizziness, sleep & behavioral disturbances,rash
- Higher treatment doses: Leukocytosis, thrombocytopenia, aminotransferase elevations, arrhythmias, bradycardia
Contraindications
- Patients with history of: Epilepsy, psychiatric disorders, arrhythmia, cardiac conduction defects, sensitivity to related drugs
- DO NOT coadminister with quinine, quinidine or halofantrine
- Considered safe in young children & pregnancy
11
Q
Primaquine
A
- Drug of choice for eradication of dormant liver forms of P. vivax and P. ovale
- Also used for chemoprophylaxis (all strains)
Clinical Applications
- Therapy of acute vivax and ovale malaria
- Terminal prophylaxis of vivax and ovale malaria; Only available agent active against dormant liver forms of P. vivax and P. ovale
- Chemoprophylaxis: protection against falciparum & vivax (toxicities are a concern – reserved for when other drugs cannot be used)
- MOA: Not completely understood (primaquine metabolites believed to act as oxidants, disrupting mitochondria and binding to DNA)
PK
- Oral
- Metabolites have less antimalarial activity but more potential for inducing hemolysis
Resistance: Resistant strains may require therapy to be repeated & dose to be increased
12
Q
Primaquine - Adverse
A
- Generally well tolerated
- Infrequent (nausea, epigastric pain, abdominal cramps, headache)
- Rare (leukopenia, agranulocytosis, leukocytosis, cardiac arrhythmias)
- Hemolysis or methemoglobinemia (especially in G6PD deficient patients)
- For severely G6PD deficient patients withhold therapy & treat relapses
- DO NOT use during pregnancy
13
Q
Malarone including adverse
A
- Malarone = atovaquone + proguanil
- Clinical Applications: Treatment & prophylaxis of P. falciparum
Antimalarial Action
- Active against tissue & erythrocytic schizonts
- Chemoprophylaxis can be started 1-2 days before travel and discontinued 1 week after exposure
MOA
• Disrupts mitochondrial electron transport
Pharmacokinetics: Oral only
Adverse Effects
- Generally well tolerated
- Abdominal pain, nausea, vomiting, diarrhea, headache,rash
- Do not use in pregnancy
14
Q
Inhibitors of Folate
A
- Pyrimethamine:
- Act slowly against erythrocytic forms of all
malaria species
* inhibit plasmodial dihydrofolate reductase
- Proguanil: Some activity against hepatic forms
- Sulfadoxine:
- Weakly active against erythrocytic schizonts
- inhibit dihydropteroate synthase
15
Q
Inhibitors of Folate synthesis
A
Clinical Applications
- Chemoprophylaxis: only in combination. Proguanil + chloroquine = no longer recommended
- Intermittent Preventive Therapy: high-risk patients receive intermittent therapy regardless of infection status
- Treatment of chloroquine-resistant falciparum malaria : pyrimethamine-sulfadoxine commonly used. DO NOT use for severe malaria
**PK: **Oral
**Resistance: **Relatively common for P. falciparum
