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1. ANTIMALARIAL DRUGS
 Malaria is caused by parasites belonging to the genus
Plasmodium
Four main species of plasmodia
Plasmodium vivax
Plasmodium falciparum
Plasmodium ovale
Plasmodium malariae
 P. falciparum is responsible for nearly all
serious complications and deaths.
 Drug resistance is an important therapeutic
problem
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2. The life cycle of the malaria parasite
Sporozoites (the asexual form of the parasite) are introduced into
the host following insect bite and these develop in the liver into:
 Primary tissue schizonts (the pre-erythrocytic stage), which
liberate merozoites-these infect RBCs, forming motile
trophozoites, which, after development, release another batch of
erythrocyte-infecting merozoites, causing fever; this constitutes
the erythrocytic cycle
 Secondary tissue schizonts (Dormant hypnozoites), which
may liberate merozoites later (the exoerythrocytic stage) – for
vivax and ovale only – responsible for relapse
Some merozoites develop into gametocytes, the sexual forms
of the parasite. When ingested by the mosquito, these give rise
to further stages of the parasite's life cycle within the insect
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3. 3
1a: entry of sporozoite into liver cell; 2a and 3a development of the
schizont in liver cell; 4: rupture of liver cell with release of
merozoites;5:entry of merozoites into a red cell;6: trophozoite in red
cell; 7/8: development of schizont in red cell; 9:rupture of red cell with
release of merozoites, most of which parasitise other red cells; 10-12:
entry of merozoites into red cells and development of male and female
gametocytes:1b: resting form of parasite in liver (hypnozoite);2b/3b:

4. Antimalarial drugs
 Classification in terms of the action against the different stages of
the life cycle of the parasite
 Blood schizonticidal agents
 Tissue schizonticidal agents
 Causal prophylactic drugs
 Terminal prophylactic drugs
A. Drugs used to treat the acute attack (blood schizonticidal agents)
◦ Produce a suppressive or clinical cure, act on the erythrocytic
forms of the plasmodium
◦ Cure for P. falciparum and P. malariae (no exoerythrocytic
stage)(non hypnotics stage)
◦ They suppress the acute attack but exoerythrocytic forms can
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5. Include:
 Quinoline methanols: quinine, mefloquine
 4-aminoquinoline: chloroquine, amodiaquine
 Phenanthrene methanols: halofanthrine, lumefanthrine
 Sulfadoxine +Pyremethamine - fansider
 Antibiotics: TTC, doxycycline, clindamycin, sulfadoxine
 Sesquiterpene endoperoxides(artemisinins):
artemether, dihydroartemisinin, artesunate,…
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6. B. Drugs that effect a radical cure/tissue
schizonticidal agents
 Affect the exoerythrocytic hypnozoites (liver
stage) and result in a 'radical' cure of P. vivax
and P. ovale
 8-aminoquinolines: primaquine, tafenoquine
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7. C. Drugs used for chemoprophylaxis/ causal prophylactic drugs
 Block the link between the exoerythrocytic stage and the
erythrocytic stage, and thus prevent the development of
malarial attacks
 Given to individuals who intend travelling to an area
where malaria is endemic.
 Administration should start at least 1 wk before entering
the area and should be continued throughout the stay and
for at least a month afterwards
 Include: chloroquine, mefloquine, proguanil,
chloroguanide, pyrimethamine, dapsone and doxycycline
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8. D. Drugs used to prevent transmission/terminal
prophylaxis
 Preventing transmission by the mosquito and
thus diminishing the human reservoir of the
disease
 Rarely used for this action alone
GAMETOCIDAL AGENTS: prevent human to
mosquito transmission: primaquine, artimisinin,
but chloroquine & quinine have moderate
activity
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9. Mechanisms of antimalarial drugs
MECHANISM DRUGS
Interference with parasite heme metabolism
↓hemozoin (harmless) production⇒↑heme
conc (toxic to the parasite) ⇒ membrane
damage
Chloroquine,
amodiaquine,
mefloquine, quinine
Block mitochondrial electron transport chain Atovaquone,
tafenoquine
Inhibit or antagonize folic acid metabolism
 Inhibit folic acid synthesis from PABA Sulfadoxine, dapsone
 Inhibit conversion of folic acid to THF
(inhibit DHFR)
Pyrimethamine,
proguanil
Production of free radicals that damage parasite
membrane and alkylation of proteins and
inhibition of a parasite calcium ATPase
Artemisinin derivatives
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10. CHLOROQUINE
 Has been the drug of choice for both treatment and
chemoprophylaxis of malaria since the 1940s
 but its utility against P.falciparum has been seriously compromised by
drug resistance
 Effective against the erythrocytic forms of all four plasmodial
species - no effect against sporozoites, hypnozoites
 1000mg at time 0, 500mg after 6 hrs, 500mg daily for next two
days (4, 2, 2,2) b/c 1 tab 250 mg.
Therapeutic uses: malaria (acute attack – DOC for non
falciparum and sensitive falciparum malaria;
chemoprophylaxis); Amebic liver abscess; rheumatoid arthritis
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11. Adverse effects
 N,V, dizziness and blurring of vision
 Large dose: retinopathies and hearing loss
 Bolus IV injections ⇒ hypotension and, if high doses are
used, fatal dysrhythmias, a single dose of 30 mg/kg may
be fatal
 Hemolysis in G6PD-deficient persons
Drug interaction: The antidiarrheal agent kaolin and Ca,
Mg - containing antacids reduce absorption
 Chloroquine is considered to be safe for use by pregnant
women and young children
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12. QUININE
 Obtained from cinchona bark (d-isomer of quinine –
quinidine)
 Acts primarily as blood schizonticidal; gametocidal for
p.vivax, p.oavle; not effective against sporozoite & liver
stage parasite
 DOC for severe illness due to chloroquine resistant &
MDR strains of p.falciparum
 Other action in the host: depressant action on the heart, a
mild oxytocic effect on the uterus in pregnancy, a slight
blocking action on the NMJ and a weak antipyretic effect
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13. Clinical use of quinine
 Quinine dihydrochloride or quinidine gluconate
(Parenteral preparations – slow IV) is DOC for
severe falciparum malaria combined with
doxycycline/clindamycin
 Quinine sulfate (oral) DOC for uncomplicated
falciparum malaria; commonly used with most often
doxycycline or, in children & pregnant, clindamycin
 First-line therapy, in combination with clindamycin,
in the treatment of babesial infection
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14. Adverse effects of quinine
 Cinchonism: a syndrome causing tinnitus, nausea, headache,
dizziness, flushing, rash
 Severe hypoglycemia (↑insulin release)
 Prolonged therapy: visual and auditory abnormalities, V, D
 Hypersensitivity reactions include skin rashes, urticaria,
angioedema, and bronchospasm
 Hematologic abnormalities include hemolysis (especially in
G6PD deficiency), leukopenia, agranulocytosis, and
thrombocytopenia
 Black water fever (rare but severe - includes marked hemolysis
& hemoglobinuria)
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15. Quinine continued
Contraindications and cautions
 Discontinued if severe cinchonism, hemolysis,
hypersensitivity
 Tinnitus and optic neuritis
 Absorption may be decreased by Al containing
antacid
 Quinine increase serum level of warfarin and
digoxin
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16. MEFLOQUINE
 Blood schizonticidal active against P. falciparum and P.
vivax
 Not active against hepatic stages or gametocytes
 Effective against chloroquine-resistant strains of P
falciparum and other species
 Although toxicity is a concern, mefloquine is one of the
recommended chemoprophylactic drugs for use in most
malaria-endemic regions with chloroquine-resistant strains
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17. Mefloquine continued…
Adverse drug reaction
 High doses: GI disturbances (50% complain) –
N,V, D, abdominal pain; CNS side effects-
giddiness, confusion, insomnia, seizures,
psychosis, depression; ECG abnormalities and
cardiac arrest if taken with quinine/quinidine/beta
blockers/halofanthrine
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18. PRIMAQUINE
 Active against hepatic stages of all human malarial parasite
(liver hypnozoites)
 Can effect a radical cure of P. vivax and P. ovale malaria in
which the parasites have a dormant stage in the liver
 Has a gametocidal action and is the most effective
antimalarial drug for preventing transmission of the disease
in all species of plasmodia
 It doesn’t affect sporozoites and little effect against
erythrocytic stage parasites; so often used in conjunction
with blood schizonticide
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19. Therapeutic uses of primaquine
 Primaquine is an 8-aminoquinoline for radical cure of
vivax and ovale
 Terminal prophylaxis
 Pneumocystis jiroveci infection: in combination with
clindamycin
ADRs: GI effects (nausea, epigastric pain, abdominal cramps),
headache; more serious but rare adverse effects include
leukopenia, agranulocytosis, leukocytosis, and cardiac
arrhythmias; large doses may cause methaemoglobinemia
with cyanosis; haemolysis (G6PD deficient patients); avoid in
pregnancy as the fetus is relatively G6PD deficient
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20. ANTIBIOTICS: TETRACYCLINES, CLINDAMYCIN
 Tetracycline and doxycycline are active against erythrocytic
schizonts of all human malaria parasites; not active against liver
stages
 Doxycycline is commonly used in the treatment of falciparum
malaria in conjunction with quinidine or quinine
 Doxycycline has also become a standard chemoprophylactic
drug
 Clindamycin is slowly active against erythrocytic schizonts and
can be used in conjunction with quinine or quinidine in those for
whom doxycycline is not recommended, such as children and
pregnant women 20

21. LUMEFANTRINE
 Blood schizonticidal related to an older compound,
halofantrine
 Blood schizonticidal agent
 Available as a fixed-dose combination with artemether
as Coartem in some countries
 Coartem is highly effective in the treatment of
falciparum
 Coartem has recently been selected as the first-line
therapy for falciparum malaria in many African countries
 Coartem also used for P.vivax
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22. ARTEMESININ AND RELATED COMPOUNDS
 Sesquiterpene lactones derived from the herb qing hao, a traditional Chinese
remedy for malaria
 Artemisinin (poorly soluble chemical extract from Artemisia)
 Its analogs: artesunate (water-soluble derivative), artemether and artether
– lipid soluble, have higher activity and are better absorbed
Oral and intravenous (IV) preparations are available, but
the short half-lives preclude their use in chemoprophylaxis
 Artemisinin and analogs are very rapidly acting blood schizonticides
against all human malaria parasites
As a class, the artemisinins are potent and fast-acting
antimalarials
 Coartem= fixed dose combination of 20 mg artemether & 120 mg
lumefantrine,
 Taken 2 tabs time 0, 2 tabs after 8 hrs, then 2 tabs bid for two days
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23.  have no effect on hepatic stages
 Have some gametocidal activity
 Role in the treatment of chloroquine resistant,
multidrug-resistant P.falciparum malaria, quinine-
resistant strains and cerebral malaria
 When used alone artemisinins are associated with a high level
of parasite recrudescence after short-course therapy
ADRs: better tolerated than most antimalarials; the most common
adverse effects have been nausea, vomiting, and diarrhea
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