Pharmacology - Antimalarials

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Parasite Life Cycle - P. Falciparum and P. malariae

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- one cycle of liver cell invasion
- liver infections ceases in less than 4 wks
- only erythrocytic parasites have to be eliminated

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Parasite Life Cycle - P. vivax and P. ovale

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- have dormant hepatic stage
- erythrocytic AND hepatic parasites have to be eliminated

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P. falciparum - sx and signs

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- most severe disease (microvascular effects) and can be fatal if untreated
- cerebral malaria (irritability --> seizures --> coma)

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Major Antimalarial Drugs

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

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Chloroquine

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DOC for BOTH TX AND PROPHYLAXIS OF MALARIA
- use is severely compromised by drug resistance
- antimalarial action = highly effective blood schizonticide; NOT active against liver stage parasites

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Chloroquine - MOA / PK

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- concentrates in parasite food vacuoles
- prevents biocrystallization of Hb breakdown product heme --> non-toxic hemozoin

PK: oral; excreted in urine

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Chloroquine - Resistance/Clinical app/ AE

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Resistance: P. falciparum - mutations in putative transporter, PfCRT

Clinical app: DOC in tx of NON-FALCIPARUM and SENSITIVE FALCIPARUM MALARIA; Preferred chemoprophylactic in areas w/o resistant falciparum

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Chloroquine - AE / CI

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AE: pruritus (Africans), Hemolysis in G6PD def people, can cause electrocardioographic changes

CI: pts w/ PSORIASIS or PORPHYRIA; RETINAL or VISUAL FIELD ABNORMALITIES

SAFE IN PREGNANCY AND YOUNG CHILDREN

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Quinine and Quinidine

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- FIRST-LINE THERAPIES FOR SEVERE FALCIPARUM DISEASE
- resistance uncommon but inc
- derived from cinchona tree bark
- quinidine is a stereoisomer of quinine
- Antimalarial action: rapidly-acting, highly effective blood schizonticide

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Quinine and Quinidine - MOA / PK

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MOA - not fully resolved (maybe similar to chloroquine - acc of toxic free heme)

PK - quinine: rapidly abs orally and well dist; IV admin for severe infections

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Quinine and Quinidine - Resistance and Clinical Applications

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Resistance: inc problem; already common in some areas of SE Asia

Clinical App:
- PARENTERAL tx of SEVERE FALCIPARUM MALARIA
- ORAL tx of FALCIPARUM MALARIA (alt in chloroquine-resistant areas)

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Quinine and Quinidine - AE

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- Cinchonism - tinnitus, headache, nausea, dizziness, flushing, visual dist
- HS - skin rashes, urticaria, angioedema, bronchospasm
- Hematologic abnormalities - hemolysis (G6PD def), leukopenia, agranulocytosis, thrombocytopenia
- Hypoglycemia - stimulation of insulin release
- Uterine contractions - but still DOC for severe falciparum malaria in pregnancy
- Severe Hypotension - too rapid IV infusion
- ECG abnormalities - QT prolongation
- Blackwater fever - hemolysis and hemoglobinuria (likely HS rxn)

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Quinine and Quinidine - CI

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- Discontinue if signs of severe cinchonism, hemolysis, HS
- Avoid if possible in pts w/ visual or auditory problems
- Use w/ caution in pts w/ underlying cardiac abnormalities
- DONT use w/ mefloquine
- can raise plasma levels of warfarin and digoxin
- reduce dose in renal insuff.

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Mefloquine

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- Effective against many CHLOROQUINE-RESISTANT strains
- Chemically related to quinine
- MOA unknown
- PK: oral only; highly protein bound, ext dist, and eliminated slowly --> single dose tx

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Mefloquine - Resistance / Clinical App

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Resistance - uncommon; assoc w/ resistance quinine but not chloroquine

Clinical App
- Chemoprophylaxis - against most strains of P falciparum
- Treatment - NOT appropriate for tx severe or complicated malaria
- Mefloquine + artesunate = uncomplicated malaria in regions of SE Asia

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Mefloquine - AE

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Weekly dosing - nausea, vomiting, dizziness, sleep, behav dist, epigastric pain, diarrhea, abd pain, headache, rash

Higher treatment doses - Leukocytosis, thrombocytopenia, aminostransferase elevations, arrhythmias, bradycardia

SERIOUS NEUROPSYCHIATRIC TOXICITIES (depression, confusion, acute psychosis, or seizures) in <1/1000

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Mefloquine - CI

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- pts w/ history of epilepsy, psychiatric disorders, arrhythmia, cardiac conduction defects, sensitivity to related drugs

DO NOT COADMIN QUININE, QUINIDINE, or HALOFANTRINE

safe in young children and pregnancy

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Primaquine

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DOC for ERADICATION OF DORMANT LIVER FORMS OF P. VIVAX and P. OVALE

ALSO CHEMOPROPHYLAXIS (ALL STRAINS)

antimalarial action - only agent against dormant liver forms of p vivax and p ovale

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Primaquine - MOA / PK

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MOA: not sure; metabolites act as oxidants possibly

PK - oral; rapidly met and excreted in urine; metabolites = less antimalarial activity but more potential for inducing hemolysis

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Primaquine - Resistance / Clinical App

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Resistance - exists; may require therapy to be repeated or dose increased

Clinical app:
- THERAPY OF ACUTE VIVAX AND OVALE MALARIA
- terminal prophylaxis of vivaz and ovale malaria
- Chemoprophylaxis - protection against falciparum and vivax (when other drugs cant be used)

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Primaquine - AE / CI

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AE - well tolerated
- infrequent (nausea, epigastric pain, abd cramps, headache)
- rare (leukopenia, agranulocytosis, leukocytosis, cardiac arrhythmias)
- hemolysis or methemoglobinemia (esp G6PD def)

- CI - G6PD DEFICIENCY, PREGNANCY

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Primaquine and G6PD Def

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- should test for def before giving primaquine
- severely G6PD def pts = w/hold therapy and treat relapses

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Atovaquone

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Malarone = atovaquone + proguanil

Antimalarial action - active against tissue and erythrocytic schizonts
- Chemoprophylaxis can be discontinued 1 wk after exposure

MOA - disrupts mitochondrial electron transport chain

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Atovaquone - PK / Clinical App / AE

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PK: oral (inc w/ fatty food)

Clinical App: Malarone = tx and prophylaxis of P. falciparum

AE: well tolerated

Safety in pregnancy = Category C

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Inhibitors of Folate Synthesis

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- used in combination regimens
- Include Pyrimethamine, Proguanil, Sulfadoxine
- Antimalarial action
~ Pyrimethanine + proguanil = act slowly against erythrocytic forms of all malaria species
~ Proguanil = SOME activity against hepatic forms
~ Sulfonamides = weakly active against erythrocytic schizonts

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Inhibitors of Folate Synthesis - MOA / PK

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Pyrimethamine and proguanil = inhibit plamodial dihydrofolate reductase

Sulfonamides = inhibit dihydropterate synthases

PK = oral; pyrimethamine has longest half-life (3-5 days)

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Inhibitors of Folate Synthesis - Resistance / Clinical App

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Resistance: relatively common for P falciparum

Clinical App:
- Chemoprophylaxis - only in combination; Proguanil + chloroquine = no longer rec.
- Intermittent Preventive Therapy - high risk pts receive intermittent therapy regardless of infection status
- Tx of Chloroquine-resistant falciparum malaria - pyrimethamine-sulfadoxine commonly used (DO NOT USE FOR SEVERE MALARIA)

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Inhibitors of Folate Synthesis - AE

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- well tolerated
- proguanil - mouth ulcers, alopecia
- pyrimethanine-sulfadoxine - erythema multiforme, Steven Johnson syn, toxic epidermal necrolysis
- sulfadoxine - hematologic, GI, CNS, derm and renal toxicity
- Pregnancy:
PROGUANIL = SAFE
PYRIMETHANINE-SULFADOXINE = SAFE

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Doxycycline / Tetracyclines

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- Active against ERYTHROCYTIC SCHIZONTS OF ALL HUMAN MALARIA PARASITES
- NOT active against liver stage

Clinical app: Doxy + quinine = tx of falciparum malaria

used to complete tx course after severe malaria tx w/ quinine, quinidinee, or artesunate

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Doxycycline / Tetracylcine - AE

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GI, candidal vaginitis, photosensitivity, discoloration, hypoplasia of teeth, stunting of growth, fatal hepatotoxicity (in pregnancy)

DO NOT USE IN PREGNANCY OR CHILDREN LESS THAN 8

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Artemisinin

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- Derived from Qinghaosu plant
- Artesunate - oral, IV, IM, and rectal
- Artemether - oral, IM, and rectal
- Dihydroartemisinin - oral

MOA - prod of free radicals w/in plasmodium food vacuole, following iron-catalyzed cleavage of drugs endoperoxide bridge by heme iron; or inhibition of parasitic calcium ATPase

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Artemisinin - Clinical App / AE

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Clinical App: tx of severe, MDR falciparum malaria
- NO effect on hepatic stages

AE: safe; very high doses - neurotoxicity, QT prolongation

Can be used in trimesters 2 and 3 of pregnancy

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Other Antimalarials

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Clindamycin
- can be used as alt to doxycycline

Halofantrine
- against erythrocytic stages of all parasites
- use limited by irregular abs and cardiac toxicity
- TERATOGENIC

Lumefantrine
- against erythrocytic stages of all parasites
- avail only as fixed-dose comb w/ artemether
- causes minor QT prolong

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CDC Malarial Guidelines

- Uncomplicated Malaria / P. Falciparum - Chloroquine Resistant or unknown

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- Atovaquone-proguanil
- Artemether-lumefantrine
- Quinine + doxycycline
- Mefloquine

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CDC Malarial Guidelines

- Uncomplicated Malaria / P. Falciparum - Chloroquine Sensitive

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- Chloroquine / hydrochloroquine

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CDC Malarial Guidelines

- Uncomplicated Malaria / P. malariae

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- Chloroquine / hydrochloroquine

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CDC Malarial Guidelines

- Uncomplicated Malaria / P. vivax or P. ovale

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- Chloroquine + Primaquine
- Hydroxychloroquine + Primaquine

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CDC Malarial Guidelines

- Uncomplicated Malaria / P. vivax - Chloroquine Resistant

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- Quinine + doxycycline + primaquine
- Atovaquone-proguanil + primaquine
- Mefloquine + primaquine

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CDC Malarial Guidelines PREGNANCY

- Uncomplicated Malaria

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Chloroquine sensitive: Chloroquine/hydrochloroquine

Chloroquine resistant P. falciparum - Quinine + clindamycin

Chloroquine resistant P. vivax - Quinine

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CDC Malarial Guidelines

- Severe Malaria

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- Quinidine + doxycycline or clindamycin

- investigational new drug: Artesunate + atovaquone-proguanil; Doxycycline, or mefloquine

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Malaria Chemoprophylaxis

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Chloroquine-sensitive: Chloroquine

Chloqoruine-resistant: Mefloquine