Antiprotozoal: Malaria ~ PDA

protozoa causing malaria in humans & form hypnozoites in the liver and cause relapse even after years

• plasmodium vivax

• plasmodium ovale

life cycle of plasmodium

1. Gametocytes from an infected human are transferred to a mosquito during a blood meal

2. In mosquito stomach, a zygote forms & matures = oocyst on the outside stomach wall

3. Sporozoites released from the oocyst migrate to salivary glands. During next blood meal, the mosquito transfers Plasmodium spp. sporozoites from its saliva to another human.

4. Sporozoites enter the host’s bloodstream and travel to the liver. Sporozoites replicate in the liver and then lyse infected hepatocytes, releasing merozoites.

5. Merozoites infect erythrocytes, undergoing asexual cycles of erythrocytic infection &  lysis

6. Some merozoites differentiate into gametocytes, which can be ingested by another mosquito and thereby continue the cycle of infection. P. vivax and P. ovale can form dormant hypnozoites, which can remain in infected hepatocytes for months to years before release into the circulation

Quinine Structure

• 1st known antimalarial

• is a blood schizonticide = targets something in malial life cycle

Quinine Properties

• t1/2 = 18h

• hepatic metabolism

• 70% protein binding

• 88% absorption

Quinine SE

CV: prolong QT

CNS: dizzy, fatigue, HA, disturbed sleep, nervous, ataxia [lack coordination]

Neuromuscular & skeletal: weakness & tremors

Ophthalmic: visual disturbances

Quinine MOA

disrupt the erythrocytic stage by interfering w/ parasitic hemoglobin metabolism & increasing intracellular pH

bind to heme in hemoglobin [ food source] and plasmodium can’t feed on erythrocytes

proposed mechanisms of drug action include inhibition of heme polymerization, enhancement of oxidant production, and reaction with heme to form cytotoxic metabolites.

Chloroquine Structure

Chloroquine Properties

• one weekly dose

• drug of choice [even tho resistant infections common]

Hydroxychloroquine Structure

Hydroxychloroquine Properties

• tx uncomplicated malaria caused by all EXCEPT P. knowlesi

• prophylaxis of malarias where chloroquine resistance NOT reported

Mefloquine Structure

Mefloquine Properties

• tx & prevent malaria

• one weekly dose

• begin 1 week before travel [continue till 4 weeks after travel]

• if area has chloroquine resistant P. falciparum, use this as alternative or halofantrine

Primaquine Structure

tx relapsing p. vivax or p. ovale → activity towards hypnozoites

create reactive oxidative species [ROS]

Perform testing for glucose-6 phosphate dehydrogenase (G6PD) deficiency prior to tx

Tafenoquine Structure

prevent relapse of malaria in pt >16yo who is recieving antimalial tx for acute p. vivax [hypnozoites]

create reactive oxidative species [ROS]

Perform testing for glucose-6 phosphate dehydrogenase (G6PD) deficiency prior to tx

Atovaquone Structure

interfere w/ pyrimidine synthesis

Proganil Structure

prodrug [metabolized to cyclogaunil [active dihydrofolate reductase inhibitor]

daily use

used for 1 week after leaving malaria zone [instead of 4 weeks]

Atovaquone/Proganil Combo [Malarone] MOA

effective against P. falciparum including strains resistant to chloroquine and mefloquine

P ~ active against hepatic stage of malaria

A ~ inhibits coenzyme Q electron transfer to Cytochrome bc1

• no electron transfer = oxidized DHOD can’t be regenerated [DHOD needed for pyrimidine synthesis]

Artemisinin Structure

• makes free radicals

Artemisinin Properties

• used in artemisinin=based combo therapy [ACT]

  • WHO reccomend tx for malaria

Artemisinin MOA

• alkylation of macromolecules such as heme & proteins = __ = toxic to plasmodia

Artemether Structure

prodrug

Artemether Properties

• tx acute, uncomplicated malaria due to P. falciparum

• prodrug [right is active metabolite]

• both cmpd are blood schizonticides

• effective against chloroquine-sensitive & resistant P. falciparum

Lumefantrine Structure

Lumefanterine Properties

inhibits formation of B-hematin by forming complex w/ hemin → ferripoto porphyrin w/ Cl

Artesunate Structure

• makes free radicals

Artesunate Properties

• tx severe malaria [1st-line]

• given IV, IM, PO, Rectum [CDC recommends IV]

• same MOA as artemisinin [toxic to plasmodia]

Doxycycline Structure

Doxycycline MOA

• bind 30S subunit & block bind of tRNA → mRNA

Doxycycline Properties

• prophylaxis in short-term travelers [<3 mo] in area w/ chloroquine- resistant P. falciparum

• begin 1-2d prior to travel, QD during travel + 4 weeks after returning home

Site of Action of Antimalarial Meds for Short-Term Travel

• Schizontes= multinucleated stages of parasites that undergo mitotic division within host cell

• Hepatic-stage schizonticides such as atovaquone–proguanil and primaquine kill malaria parasites during the brief period of initial active development within hepatocytes in the liver, and they act on the liver schizonts of all 4 species of organisms that cause human malaria.

• Only primaquine and tafenoquine are able to kill quiescent hypnozoites (Plasmodium vivax and P. ovale only), thus preventing secondary attacks (relapses) of clinical malaria.

• As compared with other drugs, atovaquone–proguanil and primaquine each act at two separate points in the life cycle. Atovaquone–proguanil acts on hepatic schizonts during initial infection but does not act on hypnozoites, so it does not prevent late-onset relapses of P. vivax and P. ovale.

• Blood-stage schizonticides such as atovaquone–proguanil, doxycycline, mefloquine, and chloroquine interrupt schizogony within red cells, preventing clinical manifestations of malaria infection. Not all parasite life-cycle stages are shown in this figure.