ANTIMALARIAL AGENTS

BY DR MARY ONYANGO
 INTRODUCTION
• Malaria is caused by plasmodium spp
– P. falciparum – responsible for the serious complications
and death
– P. vivax
– P. ovale
– P. malariae
• P. falciparum and p. malariaea only have one cycle
of liver cell invasion
• P. vivax and ovale have a dormant hepatic stage ,
the hypnozoites and associated with relapses
 Cont.
• Life cycle
– Mosquito
• Gametocytes ----- sporozoites
– Human host
• Exoerythrocytic stage
– Sporozoite – tissue schizonts ---- merozoits
• Erythrocytic stage
– Repeated infection of the erythrocytes
– Development of gametocytes
Malaria Life Cycle Life Cycle

Sporogony
Oocyst
Sporozoite
s Mosquito
Salivary Gland
Zygote

Sporozoites Hypnozoites
(for P. vivax
and P. ovale)
Gametocytes
Exo-
erythrocytic
(hepatic) cycle
Merozoites
Erythrocytic
Cycle Merozoites

Schizogony
 Terminologies
• Clinical cure- refers to relief of clinical
manifestation without necessary eradicating
the parasites in the body common especially
in those species associated with relapses
• Radical cure- eradication of both the
exoerythocytic and erythrocytic of the
malaria parasites from the body (complete
cure.) In p. falciparum, clinical cure and radical
cure mean the same
 Terminologies cont.
• Causal prophylaxis- refers to prevention of the
development of the tissue forms of the malaria parasites
hence no erythrocytic stage is formed and therefore
transmission of malaria is prevented e.g. primaquine
• Clinical prophylaxis-refers to suppression of parasitimea
and its symptoms e.g. chloroquine, it does not act on the
tissue forms
• Tissue schizonticides- are drugs that are used for casual
prophylaxis. They kill the larva stage and prevent the
development of clinical malaria and also transmission of
malaria through mosquito bites.
 Terminologies cont..
• Blood schizonticides-are drugs that are used
for clinical or suppressive cure. They act on
the erythrocytic /asexual stage of the malaria
parasites to interrupt schizogony and
terminate the clinical
• Gametocytocides: are drugs that destroy the
sexual erythrocytic stage forms of malaria and
prevent transmission of malaria by the
mosquitoes
Eradication of
dormant
 P. falciparum
• Causes malignant tertiary malaria (fatal if not promptly treated)
• The characteristic features:
– Severe headaches
– Pyrexia- fevers that recur after every 48 hours. These bouts of fever coincide with
release of merozoites form the erythrocytes-known as clinical malaria
– Delayed treatment may lead to involvement of organs e.g. the brain, the patient
presents with manic state (convulsions and hallucinations) and an irreversible state of
shock due to vascular collapse (because the CVS is involved)
– Kidney involvement-the patient presents with jaundice and passes out dark coloured
urine (black water fever.) The dark colouration is due to excess heme in urine and
precipitation of the heme pigments in the renal tubules may lead to blockage causing
anuria which may progress to renal failure
– The pt presents with haemolytic anaemia- due to rapid destruction of erythrocyts
– In light skinned persons there may be increase in pigmentation by the released heme
– Hepatosplenomegally may occur due to reticuloendothelical hyperplasia of the
spleen and the liver
 P. Falciparum cont…
prodromal signs
• Lumbar and back pains
• Increased malaise and fatigue
• Limb pains
• Chills
• Mild sweating
• Anorexia
• Nausea and vomiting
• Some patients have diarrhea
• Some pts have flashy faces and shiny eyes especially in children
• Dry cough
• Diffuse mild pain in the abdomen or in the epigastric region
• Anaemia
• Any temperature 38.5⁰c in children may lead to convulsions and if at 40⁰c the child may go
to coma. The temperature may lead to irreversible neurological damage (the children may
continue getting seizures that are not epileptic in nature later in life)
• Low blood pressure
 P. Vivax

• Causes benign tertiary malaria

• It is mild
• Has low mortality and mobidity even in
untreated pts
• Has erytrhocytic cycle of 48 hours
• Usually characterised by delayed relapses that
may occur as long as 2 years after the primary
attack
 P ovale and P malariae
• P.Ovale
• Also causes benign tertiary malaria which is even
milder that for p.vivax
• Has an erthrocytic cycle of 48 hours
• characterised by relapses
• P.Malariae
• Causes benign quantain malaria which has a 72hour
cycle
• It has no exocrythrocytic stage
• The clinical attack may occur years after infection
 Classes of antimalarial agents
• 4- aminoquinolines –chloroquine & amodiaquine
• Quinoline methanols – quinine , mefloquine
• 8- aminoquinolines - primaquine
• Folate antagonists – proguanil, pyrimethamine
• Antibiotics – doxycycline, clindamycin
• Phenanthrene methanols - halofantrine
• Aryl alcohol- lumefantrine
• Sesquiterpene lactone endoperoxides- artemisinin
and derivatives
 Drug Classification
• Classified by their selective actions on
different phases of the parasite life cycle:
1. Tissue schizonticides: eliminate developing or
dormant liver forms.
2. Blood schizonticides: act on erythrocytic
parasites.
3. Gametocides: kill sexual stages and prevent
transmission to mosquitoes.
• No one available agent can reliably effect a
radical cures.
 Uses

Prevent
prophylaxis Cure
transmission

Suppress
causal
Gametoc Sporont Blood
ive ides ocides schizontocides

blood tissue
schizontocide schizontocide
s s
 1- Prophylactic:-to
prevent clinical attack
1. Suppressive prophylaxis:-
use of blood
schizontocides to prevent
acute attack
2. Causal prophylaxis:-use
of tissue schizontocides
to prevent the parasite
from establishing in the
liver
2-Curative:-suppressive treatment of
the acute attack usually with blood
schizontocides.
3-Prevention of transmission:-
eradication of infection in mosquitos
using gametocytocides or
sporontocides.
4-Prevention of relapse:-
Primaquine
 4- aminoquinolines
• Chloroquine
• Hydroxychloroquine
• Amodiaquine

• Highly effective as blood schizonticides

• Moderately effective against gametocytes of p.
vivax, ovale , malariae but not against those of p.
falciparum
• Not effective against the liver stages
Chloroquine and amodiaquine
potent blood schizontocide
 4-aminoquinolines
mechanism of action
• Asexual malaria parasites flourish in the host
erythrocytes by digesting haemoglobin in their acidic
food vacuoles and this generates free radicals and heme
(ferriprotoporphyrin IX) which are highly reactive
• These are converted to an insoluble unreactive pigment
– the hemozoin
• The 4-aminoquinolines and probably the other
quinolines, concentrate in the parasite food vacuole,
preventing the conversion of heme to hemozoin
• This ellicit parasite toxicity due to the build up of free
heme
Mechanism of action
Control symptoms

Chloroquine
• A synthetic 4-aminoquinoline formulated as the
phosphate salt for oral use or HCl for parenteral use
• Pharmacokinetics
– Rapidly and almost completely absorbed from the
gastrointestinal tract.
– Very large apparent volume of distribution of 100-1000
L/kg.
– Necessitate the use of a loading dose to rapidly achieve
effective serum concentrations.
– Slowly released from tissues and metabolized.
– Principally excreted in the urine.
• Pharmacological Effects
1. Antimalarial action:
– highly effective blood schizonticide.
– Moderately effective against gametocytes of P vivax, P ovale, and P
malariae but not against those of P falciparum.
– not active against liver stage parasites.
 Mechanism:
 plasmodium aggregates chloroquine.
 chloroquine incorporated into DNA chain of plasmodium → inhibit
proliferation.
 chloroquine prevents the polymerization of the hemoglobin breakdown
product, heme, into hemozoin and thus eliciting parasite toxicity due to the
buildup of free heme.
 pH↑→ plasmodium protease activity↓
 Resistance: very common among strains of P falciparum and uncommon but
increasing for P vivax. The mechanism of resisitance to chloroquine is resistant
strains excretes drug more rapidly.
1. Killing Amoebic trophozoites : chloroquine reaches high liver
concentrations.
2. Immunosuppression action:
• Clinical Uses
1. Treatment: nonfalciparum and sensitive
falciparum malaria. Primaquine must be added
for the radical cure of P vivax and P ovale,
because chloroquine does not eliminate
dormant liver forms of these species.
2. Chemoprophylaxis: for without resistant
falciparum malaria in malarious regions.
3. Amebic liver abscess: not effective in the
treatment of intestinal or other extrahepatic
amebiasis.
• Adverse Effects and Cautions
– Usually very well tolerated, even with prolonged use.
– Pruritus is common.
– Nausea, vomiting, abdominal pain, headache, anorexia,
malaise, blurring of vision, and urticaria are uncommon.
– Dosing after meals may reduce some adverse effects.
– Rare reactions include hemolysis in G6PD-deficient
persons, impaired hearing, confusion, psychosis, seizures,
hypotension, ECG changes.
– teratogenesis
 Cont..
Contraindications:
•Psoriasis or prophyria
•Visual field abnormalities or myopathy
•Ca and Mg containing antacid interfere with absorption
•Used with caution in liver disease or neurologic or hematologic
disorders.

Other uses:
It is a disease modifying antirheumatoid drug.
(6-9 month)
SLE
In amebic liver abscess
 Quinoline methanols
• Quinine
• Quinidine
• mefloquine
 Quinine
• Quinine and quinidine remain first-line therapies for
falciparum malaria——especially severe disease.
• Quinine is an alkaloid derived from the bark of the
cinchona tree, a traditional remedy for intermittent
fevers from South America.
• Quinine is the levorotatory stereoisomer of
quinidine.
• Rapidly absorbed after oral administration.
• Metabolized in the liver and excreted in the urine.
• Pharmacological Effects
– Highly effective blood schizonticide against the
four species of human malaria paresites.
– Gametocidal against P vivax and P ovale but not P
falciparum.
– Not active against liver stage parasites.
– Depressing cardiac contractility and conduction,
lengthening refractory period, exciting uterine
smooth muscle, depressing central nervous
system, little antipyretic-analgesic effect.
• Clinical Uses: mainly for chloroquine-resistant
falciparum malaria, especially for cerebral
malaria.
– Parenteral treatment of severe falciparum malaria
– Oral treatment of falciparum malaria
– Babesiosis
• Adverse Effects and Cautions
1. Cinchonism: tinnitus, headache, nausea,
dizziness, flushing, visual disturbances
2. Cardiovascular effects: severe hypotension and
arrhythmia can follow too-rapid intravenous
infusion.
3. Idiosyncrasy: hemolysis with G6PD deficiency.
4. Others: hypoglycemia through stimulation of
insulin release, stimulate uterine contractions
 Mefloquine
• A synthetic 4-quinoline methanol that is chemically
related to quinine.
• Pharmacokinetics
– Only be given orally because severe local irritation occurs
with parenteral use.
– Well absorbed.
– Highly protein-bound, extensively distributed in tissues,
and eliminated slowly. t1/2 is 20 days.
• Pharmacological Effects:
– Strong blood schizonticidal activity against P falciparum
and P vivax, but not active against hepatic stages or
gametocytes.
• Clinical Uses
– Chemoprophylaxis:
– Treatment: mainly for chloroquine-resistant
falciparum malaria.
• Adverse Effects and Cautions
– Nausea, vomiting, diarrhea, abdominal pain——
dose-dependent
– Neuropsychiatric toxicities: dizziness, headache,
behavioral disturbances, psychosis, seizures.
– Contraindicated in epilepsy, psychiatric disorders,
cardiac condiuction defects and hypersensitivity
 8 – aminoquinolines
• Primaquine
• pamaquine
The only drug which is active against liver
hypnozoites.
MOA: produces radical cure for parasites
which have dormant stage in the liver
[P.ovale & P.vivax].
Has gametocidal action against all species.
most effective for preventing transmission of
the disease.
 ADR:- GIT disturbances, in
large doses 
methemoglobinemia with
cyanosis
Causes hemolysis in G-6-P –
dehdrogenase deficiency,
metabolites have greater
hemolytic activity

Contraindications:
•History of methemoglobinemia
•Pregnancy
• Clinical Uses
– Therapy (Radical Cure) of Acute Vivax and Ovale Malaria:
chloroquine + primaquine
– Terminal Prophylaxis of Vivax and Ovale Malaria: prevent a
relapse
– Chemoprophylaxis of Malaria: protection against
falciparum and vivax malaria. But potential toxicities of
long-term use limited its routinely administration.
– Gametocidal Action: A single dose of primaquine (45 mg
base) can be used as a control measure to render P
falciparum gametocytes noninfective to mosquitoes. This
therapy is of no clinical benefit to the patient but will
disrupt transmission
– Pneumocystis carinii infection: clindamycin+primaquine →
mild to moderate pneumocystosis
• Adverse Effects and Cautions
• Nausea, epigastric pain, abdominal cramps,
headache.
• Hemolysis or methemoglobinemia, especially
in persons with G6PD deficiency or other
hereditary metabolic defects.
 Artemisinin
• Extracted from Artemisia annua.
• Kill trophozoites of erythrocytes.
• quick and effective.
• Pass through blood-brain barrier, treatment for
cerebral malaria.
• recurrence rate is high if used alone
Artemisinin derivatives
• Artemether and Artesunate
• Dihydroartemisinin
Artemisinin is poorly soluble in
water & a fast acting blood
schizontocide.
Effective in treating severe
acute attacks, including
chloroquine –resistant &
cerebral malaria.

Artemesia annua
Artesunate[a water- soluble derivative],
artemether [synthetic analogue] have higher
activity & are better absorbed.
It damages the parasite membrane by
carbon- centered free radicals.
Used orally, Rapidly absorbed, widely
distributed,
Converted in the liver to the
active metabolite
dihydroartemisinin.
t½ of artemisinin
4h,artesunate=45min,
artemether 4-11h.

ADR:- transient heart block,

neutrophil count, brief
episodes of fever.
Neurotoxic in animal,
 Doxycycline : active against ertythrocytic
schizonts of all species
is used as a suppressive prophylactic in
areas where mefloquine resistance is
common.
Clindamycin has proved effective in the
treatment of uncomplicated falicparum
malaria, may be used in combination with
quinine.
Type 1 antifolates
sulphonamides &
sulphones , compete
with PABA.
Type
2 ,pyrimethamine &
proguanil
inhibition of
dihydrofolate
reductase.
Have slow action
against the
erythrocytic forms of
the parasite.
Pyrimethamine is
used in combination
with either dapsone
or sulfadoxine.
Sulfonamides & sulfones are active
against the erythrocytic forms of
P.falciparum
Pyrimethamine & proguanil are
slowly orally absorbed.
t½ of pyrimethamine =4d,
proguanil=16h.
Proguanil is metabolized to an active
metabolite ,cycloguanil which is
excreted in urine.
ADR:- large doses of
pyrimethamine -dapsone
combination causes haemolytic
anaemia, agranulocytosis.
In high doses pyrimethamine
mammalian dihydrofolate
reductase megaloblastic
anaemia.
Resistance → a single mutation
in the genes encoding parasite
dihydrofolate reductase.
Dapsone
 Pyrimethamine
• Pharmacokinetics
– Slowly but adequately absorbed from the gastrointestinal
tract.
– Slowly eliminated and excreted from urine.
• Pharmacological Effects
– Kill schizonts of primary exoerythrocytic stage.
– Act slowly against premature schizonts of erythrocytic stage.
– No action against gametocytes, but can inhibit development
of plasmodium in mosquito.
– Inhibit plasmodial dihydrofolate reductase → inhibiting
breeding of plasmodium.
• Adverse Effects and Cautions
– Gastrointestinal symptoms, skin rashes.
– Interfering folic acid metabolism in human →
megaloblastic anemia, granulocytopenia.
 Atovaquone-proguanil
MECHANISM OF ACTION:
• Inhibits electron transport in mitochondria resulting in the inhibition of key metabolic
enzymes responsible for the synthesis of nucleic acids and ATP.
• Resistance to atovaquone is mediated by mutations in the cytochrome b gene.
▫ However, the combination retains excellent clinical efficacy for treatment and prevention throughout
the world even in the presence of antifolate resistance

PHARMACODYNAMICS / KINETICS
• Absorption: Significantly increased with a high-fat meal
• Protein binding: >99%
• Metabolism: Undergoes enterohepatic recirculation
• Bioavailability: 32% to 62%
• Half-life elimination: 1.5-4 days
• Excretion: Feces (>94% as unchanged drug); urine (<1%)

USE : Acute oral treatment of mild-to-moderate Pneumocystis jirovecii pneumonia (PCP) in

patients who are intolerant to co-trimoxazole; prophylaxis of PCP in patients who are
 Atovaquone-proguanil
Adverse effects include:
• abdominal pain, vomiting, diarrhea, headache and
pruritis.
• Among adults in Thailand, mild asymptomatic
increases in transaminases were observed shortly
after initiating therapy, although they normalized
by day 14.
CONTRAINDICATIONS : Life-threatening allergic
reaction to atovaquone or any component of the
formulation.
 Lumefantrine and Halofantrine
• These drugs are active against most chloroquine-resistant parasites
although there is cross-resistance between halofantrine and mefloquine.
• Lumefantrine is a long-acting partner drug to artemether in a widely used
fixed-dose combination; the half-life of lumefantrine is 3 to 6 days.
• An important determinant of lumefantrine efficacy is drug level; the oral
bioavailability is highly variable and increases up to three- to four-fold
when taken with a high fat meal.
• Lumefantrine is well tolerated, with rare mild adverse reactions such as
diarrhea, nausea, abdominal pain and vomiting.
• There is no evidence of significant cardiotoxicity associated with
lumefantrine use.
• Halofantrine has been effective in chloroquine- and mefloquine-resistant
malaria, although cardiac toxicity (dose-dependent prolongation of the PR
 others
• Piperaquine – bisquinoline used together with
dihydroartemisinine