Antimalarials

Question 1

Malarial paroxysm

Answer 1

• fever, anemia, jaundice, splenomegaly, hepatomegaly
• In established infections, malarial paroxysms typically occur about every 2-3 days

Question 2

P. falciparum sx

Answer 2

• 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

Question 3

Major antimalarials

Answer 3

• Chloroquine
• Quinine and Quinidine
• Mefloquine
• Primaquine
• Atovaquone
• Sulfadoxine-pyrimethamine
• Doxycycline
• Artemisinins

Question 4

Antimalarials according to clinical status of Pt

Answer 4

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

Question 5

Chloroquine

Answer 5

• 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

Question 6

Chloroquine - Adverse

Answer 6

• 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

Question 7

Quinine and Quinidine

Answer 7

• 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

Question 8

Quinine & Quinidine - Adverse

Answer 8

• 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)

Question 9

Mefloquine

Answer 9

• 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

Question 10

Mefloquine - Adverse

Answer 10

• 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

Question 11

Primaquine

Answer 11

• 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

Question 12

Primaquine - Adverse

Answer 12

• 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

Question 13

Malarone including adverse

Answer 13

• 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

Question 14

Inhibitors of Folate

Answer 14

• 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

Question 15

Inhibitors of Folate synthesis

Answer 15

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

Question 16

Inhibitor of folate synthesis - Adverse

Answer 16

• Well tolerated (GI problems, rashes, itching)
• Proguanil (mouth ulcers, alopecia = rare)
• Pyrimethamine-Sulfadoxine (erythema multiforme, Steven-Johnson syndrome, toxic epidermal necrolysis)
• Sulfadoxine (hematologic, GI, CNS, dermatologic & renal toxicity)

Pregnancy

• Proguanil = safe
• Pyrimethamine-sulfadoxine = safe

Question 17

Doxycycline

Answer 17

• Active against erythocytic schizonts of all human malaria parasites
• NOT active against liver stage

Clinical applications

• Used to complete treatment for severe falciparum malaria (given along with quinine) after initial treatment with quinine, quinidine or artesunate
• Chemoprophylaxis against most forms: must be taken daily

Question 18

Doxycycline - Adverse

Answer 18

• GI, candidal vaginitis, photosensitivity
• Discoloration & hypoplasia of teeth, stunting ofgrowth
• Fatal hepatotoxicity (in pregnancy)
• DO NOT use in pregnancy or children < 8y (FDA Category D)

Question 19

Artemisinin

Answer 19

• Artesunate : oral, IV, IM & rectal admin
• Artemether: oral, IM & rectal admin
• Dihydroartemisinin: oral admin
• Coartem = artemether + lumefantrine

Clinical Applications

• Treatment of severe falciparum malaria (given IV)
• NO effect on hepatic stages
• Should not (in general) be used as single agent to protect against resistance

**MOA: **Appears to act by binding iron, breaking down peroxide bridges leading to generation of free radicals that damage parasite proteins.

PK:

• Very short t1/2 (IV therapy must be followed by a longer- acting agent once patient is able to tolerate oral therapy)
• If used alone, artesunate must be administered 5-7 days (otherwise recurrent parasitemia results)

Question 20

Artemisinin - Adverse

Answer 20

• Overall remarkably safe (nausea, vomiting, diarrhea)
• Very high doses: neurotoxicity, QT prolongation
• More evidence for use in 2nd and 3rd trimesters of pregnancy
• In 1st trimester can be used for treatment of severe malaria

Question 21

Other antimalarials

Answer 21

Clindamycin: Can be used as an alternative to doxycycline

Halofantrine

• Effective against erythrocytic stages of all parasites
• Use is limited by irregular absorption & cardiac toxicity
• Teratogenic

Lumefantrine

• Effective against erythrocytic stages of all parasites
• Available only as fixed-dose combination with artemether
• Causes minor QT prolongation (clinically insignificant)
• Well tolerated