Malaria

• Malaria is the most important parasitic disease of humans. 4 species of plasmodium cause human malaria:
P. falciparum, P. vivax, P. malariae, and P. ovale.
A fifth species, P knowlesi, is primarily a pathogen of monkeys but has recently been recognized to cause
illness, including severe disease, in humans in Asia.
• P falciparum is responsible for majority of serious complications and deaths. It is also the most resistant.
Parasite life cycle
1) Anopheline mosquito inoculates plasmodium sporozoites to
initiate human infection.
2) Circulating sporozoites rapidly invade liver cells, and tissue
schizonts mature in the liver (exoerythrocytic stage).
3) Merozoites are released from the liver and invade
erythrocytes. Only erythrocytic parasites cause clinical
illness.
4) Repeated cycles of infection can lead to the infection of
many erythrocytes and serious disease.
5) Sexual stage gametocytes also develop in erythrocytes
before being taken up by mosquitoes, where they develop into
infective sporozoites.

 In P falciparum and P malariae infection, only one cycle of liver cell invasion and multiplication occurs,
and liver infection ceases spontaneously in less than 4 weeks.
 So, TTTthat eliminates erythrocytic parasites will cure these infections.
 In P vivax and P ovale infections, a dormant hepatic stage, the hypnozoite, is not eradicated by most
drugs, and relapses can occur after therapy directed against erythrocytic parasites. ( Resistent)
 Eradication of both erythrocytic and hepatic parasites is required to cure these infections.
Drug classification
Tissue Schizonticides Drugs that eliminate developing or dormant liver forms.
Blood Schizonticides Drugs act on erythrocytic parasites
Gametocides: Drugs that kill sexual stages and prevent transmission to mosquitoes
 No single agent can eliminate both hepatic and erythrocytic stages
Chemoprophylaxis
1) Avoid mosquito bites.
2) Chloroquine used for chemoprophylaxis in areas infested by only chloroquine-sensitive malaria parasites
3) Mefloquine, Malarone, or doxycycline used for malarious areas.
4) Doxycycline is preferred for areas with a high prevalence of multidrug-resistant falciparum malaria.

Chloroquine
Mechanism of  The drug concentrate in parasite food vacuoles, preventing the conversion of the
heme, into hemozoin crystals leading to buildup of free heme and parasite
Action
toxicity.
 Blood schizonticide and against gametocytes
• Chloroquine is not active against liver stage parasites.
Pharmacokinetics 1) It is rapidly and almost completely absorbed from the GIT, reaches max. plasma
Conc. in about 3 hr.
2) Excreted in urine with an initial T1/2 of 3–5 days but a much longer terminal
elimination T1/2 of 1–2 months.
Resistance Mutations in a putative transporter, PFCRT (P falciparum Chloroquine resistance
transporter) which lead to efflux of chloroquine from the intracellular digestive
vacuole.
Uses  Treatment:
It is the DOC in TTT of uncomplicated non-falciparum and sensitive falciparum
malaria. It does not eliminate dormant liver forms of P vivax and P ovale, So
primaquine must be added for the radical cure of these species.
 Chemoprophylaxis:
It is the preferred chemoprophylactic agent in malarious regions without resistant
falciparum malaria.
Eradication of P vivax and P ovale requires combination with primaquine to clear
hepatic stages.
 Amebic liver abscess
Used for amebic abscesses that fail initial therapy with metronidazole.
Used in Covid -19 treatment protocol.
Adverse Effects 1) Pruritus.
2) Rare reactions include hemolysis in (G6PD)-deficient persons
3) Impaired hearing, confusion, psychosis, seizures, agranulocytosis, exfoliative
dermatitis, alopecia, bleaching of hair.
4) Hypotension, and ECG changes (QRS widening, T-wave abnormalities).
5) The long-term administration of high doses of chloroquine for rheumatologic
diseases can result in irreversible ototoxicity, retinopathy, myopathy, and
peripheral neuropathy.
5) IM injections or IV infusions of chloroquine hydrochloride can result in severe
hypotension and respiratory and cardiac arrest, and should be avoided.
Contraindications 1] It is contraindicated in patients with psoriasis or porphyria.
& Cautions 2] Should not be used in those with retinal or visual abnormalities or myopathy.
3] Should be used with caution in patients with liver, neurologic, or hematologic
disorders.
4] The antidiarrheal agent kaolin and Ca- and Mg-containing antacids interfere
with the absorption of chloroquine and should not be co-administered.
5] Chloroquine is considered safe in pregnancy and for young children.

Amodiaquine
It is closely related to chloroquine.
Effective against chloroquine-resistant strains of P falciparum.
 Toxicities, including agranulocytosis, aplastic anemia, and hepatotoxicity, have limited its use.
 Used in combination therapy with artesunate or sulfadoxine-pyrimethamine for falciparum malaria.
Piperaquine
It is combined with dihydroartemisinin for falciparum malaria, without apparent drug resistance.
It has a longer T1/2 (~ 28 days) leading to a longer period of post-treatment prophylaxis.
 Artemisinin & its derivatives
 Artemisinin is insoluble and can only be used orally.
 The most important analogs are:
Artesunate (water-soluble; oral, intravenous, intramuscular, and rectal administration).
Artemether (lipid-soluble; oral, intramuscular, and rectal administration)
Dihydroartemisinin (water-soluble; oral administration).
Pharmacokinetics  Artemisinin and its analogs are rapidly absorbed.
 Half-lives after oral administration are 30–60 minutes for artesunate and
dihydroartemisinin, and 2–3 hours for artemether.
 Artemisinin, artesunate, and artemether are metabolized to the active metabolite
dihydroartemisinin.
 Antimalarial Action
1) The artemisinins are usually given as co-formulated artemisinin-based
combination therapies to improve efficacy and prevent resistance.
2) Found as oral combination regimen Coartem (artemether-lumefantrine) or as IV
artesunate.
3) Artemisinin and its analogs are very rapidly acting blood schizonticides against
all human malaria parasites. Artemisinins have no effect on hepatic stages.
Mechanism of Cleavage of endoperoxide bridge and the production of free radicals.
action
Uses 
Artemisinin-based combination therapy is now the standard for ttt of
uncomplicated falciparum due to high efficacy, safety, and well toleration.
 Combination therapy also helps to protect against artemisinin resistance.
 The WHO recommends five artemisinin-based combinations for the ttt of
falciparum malaria:
1] Artesunate-sulfadoxine-pyrimethamine. 2] Artesunate-mefloquine
3] Artesunate-amodiaquine 4] Artemether-lumefantrine
5] Dihydroartemisinin-piperaquine
Adverse Effects & 1) The most commonly adverse effects are nausea, vomiting, diarrhea, and
Cautions dizziness, and these may often be due to malaria rather than the medications.
2) Rare serious toxicities include neutropenia, anemia, hemolysis, elevated liver
enzymes, and allergic reactions.
3) Irreversible neurotoxicity has been seen in animals, but only after doses much
higher than those used to treat malaria.
4) Embryotoxic in animal studies, but rates of congenital abnormalities, and
abortions were not elevated, compared with those of controls, in women who
received artemisinins during pregnancy.

 WHO recommendations for pregnant women.

1) Quinine plus clindamycin is recommended during the first trimester.
2) Artemisinin-based combination therapies during the 2nd and 3rd trimesters.
3) IV artesunate or quinine for the ttt of severe malaria during the first trimester.
4) IV artesunate for TTT of severe malaria during the second and third trimesters.
 Quinine & quinidine
Pharmacokinetics  After oral administration, quinine is rapidly absorbed, reaches peak plasma
levels in 1–3 hours, and is widely distributed in body tissues.
 The use of a loading dose in severe malaria allows the achievement of peak
levels within a few hours.
 Individuals with malaria develop higher plasma levels of the drug than
healthy controls, but toxicity not increased due to increased protein binding.
 T1/2 of quinine also is longer in those with severe malaria than in healthy
controls.
 Quinidine has shorter T1/2 than quinine, as a result of decreased protein
binding.
 Quinine is primarily metabolized in the liver and excreted in the urine.
Antimalarial Action  Quinine is a rapid-acting, highly effective blood schizonticide against the
& Resistance four species of human malaria parasites.
 The drug is gametocidal against P vivax and P ovale but not P falciparum.
 It is not active against liver stage parasites.
 The mechanism of action of quinine is unknown.
Uses 1) Parenteral treatment of severe falciparum malaria.
Quinine dihydrochloride or quinidine gluconate.
TTT should begin with a loading dose to achieve effective plasma Conc .
 Because of its cardiac toxicity IV quinidine should be administered slowly
with cardiac monitoring.
 Therapy should be changed to an effective oral agent as soon as the patient
has improved and can tolerate oral medications.
2) Oral treatment of falciparum malaria:
 Quinine sulfate is appropriate therapy for uncomplicated falciparum malaria.
 Quinine is commonly used with a second drug (often doxycycline or, in
children, clindamycin) to shorten the duration of use and limit toxicity.
 Quinine not generally used to treat non-falciparum malaria, as it is less
effective than chloroquine against these parasites and is more toxic.
3) Malarial chemoprophylaxis :
Quinine is not generally used in chemoprophylaxis owing to its toxicity.
4) Babesiosis :
Quinine is first-line therapy, in combination with clindamycin, in the ttt of
infection with Babesia microti or other human babesial infections.
Adverse Effects 1) Cinchonism: quinine and quinidine commonly cause tinnitus, headache,
nausea, vomiting, diarrhea, abdominal pain, dizziness, flushing, and visual
disturbances
2) Hypersensitivity reactions: skin rashe, urticaria, angioedema and
bronchospasm
3) Hematologic abnormalities: hemolysis (especially with G6PD deficiency),
leukopenia, agranulocytosis, and thrombocytopenia. IV infusions of the drugs
may cause thrombophlebitis.
4) Hypoglycemia by stimulation of insulin release.
5) Quinine can stimulate uterine contractions, especially in the third trimester.
However, this effect is mild, and quinine and quinidine remain appropriate for ttt
of severe falciparum even during pregnancy.
 6) Severe hypotension can follow too-rapid IV infusions of quinine or quinidine.
7) ECG abnormalities (QT interval prolongation), So the drug should be
administered appropriately in a monitored setting.
8) Blackwater fever (quinine) is a rare severe hypersensitivity reaction that
includes marked hemolysis and hemoglobinuria.
Contraindications 1) They should be discontinued if signs of severe cinchonism, hemolysis, or
hypersensitivity occur.
& Cautions 2) They should be avoided in patients with visual or auditory problems.
3) It must be used with great caution in those with cardiac abnormalities.
4) Quinine should not be given concurrently with mefloquine and should be
used with caution in a patient with malaria who has previously received
mefloquine chemoprophylaxis.
5) Absorption may be blocked by Al-containing antacids.
6) Quinine can raise plasma levels of warfarin and digoxin.
7) Dosage must be reduced in renal insufficiency.