MALARIA

Etiology: Four Plasmodium species are responsible for human malaria,

P. falciparum,
P.ivax,
P. ovale
P. malariae.

Epidemiology: There are about 200 million estimated global cases of malaria with a mortality of
more than one million. P. falciparum (malignant tertian malaria) and P. malariae (quartan malaria)
are the most common species and are found in Asia and Africa. P. vivax (benign tertian malaria)
predominates in Latin America, India and Pakistan, whereas, P. ovale (ovale tertian malaria) is
almost exclusively found in Africa.
BLOOD AND TISSUE PROTOZOA
Antiprotozoal Drugs
The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles
mosquito inoculates sporozoites into the human host. After initial replication in the liver (exoerythrocytic
schizogony), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony).
Multiplication of the blood stage parasites is responsible for the clinical manifestations of the disease. In the
blood, some parasites differentiate into sexual erythrocytic stages (gametocytes). The gametocytes, after
ingestion by an Anopheles mosquito during a blood meal, undergo a sporogonic cycle yielding
sporozoites.?Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle. Of note,
in P. vivax and P. ovale, a dormant stage (hypnozoites) can persist in the liver and cause relapses by invading
the bloodstream weeks, or even years later
Symptoms: The symptomatology of malaria depends on parasitemia, the presence of the organism in
different organs and the parasite burden.
The incubation period varies generally between 10-30 days.
As the parasite load becomes significant, the patient develops headache, lassitude, vague pains in the bones
and joints, chilly sensations and fever. As the disease progresses, the chills and fever become more
prominent.

The chill and fever follows a cyclic pattern (paroxysm) with the symptomatic period lasting 8-12 hours. In
between the symptomatic period, there is a period of relative normalcy, the duration of which depends upon
the species of the infecting parasite. This interval is about 34-36 hours in the case of P. vivax and P. ovale
(tertian malaria), and 58-60 hours in the case of P. malariae (quartan malaria). Classical tertian paroxysm is
rarely seen in P.alciparum: persistent spiking or a daily paroxysm is more usual.

The malarial paroxysm is most dramatic and frightening: it begins with chilly sensation which progresses to
teeth chattering overtly shaking chill, peripheral vasoconstriction resulting in cyanotic lips and nails (cold
stage) which lasts for about an hour. At the end of this period the body temperature begins to climb and
reaches 103-106 degrees F (39- 41degrees C). Fever is associated with severe headache, nausea (vomiting)
and convulsions. The patient experiences euphoria, and profuse perspiration and the temperature begins to
drop. Within a few hours the patient feels exhausted but symptomless and remains symptomatic until the next
paroxysm. Each paroxysm is due to the rupture of infected erythrocytes and release of parasites
Without treatment, all species of human malaria may ultimately result in spontaneous cure except with P.
falciparum which becomes more severe progressively and results in death. This organism causes
sequestration of capillary vasculature in the brain, gastrointestinal and renal tissues.
Chronic malaria results in splenomegaly, hepatomegaly and nephritic syndromes.

Pathology and immunology: Symptoms of malaria are due to release of massive number of merozoites into
circulation. Infection results in the production of antibodies which are effective in containing the parasite
load. These antibodies are against merozoites and schizonts. The infection also results in the activation of the
reticuloendothelial system (phagocytes). The activated macrophages help in the destruction of infected
(modified) erythrocytes and antibody coated merozoites. Cell mediated immunity also may develop and help
in the elimination of infected erythrocytes. Malarial infection is associated with immunosuppression.
Diagnosis: Diagnosis is based on symptoms and detection of parasite in Giemsa stained blood smears.

Treatment and Control: Treatment is effective with various quinine derivatives (quinine sulphate,
chloroquine, meflaquine and primaquine, etc.).
Drug resistance, particularly in P. falciparum and to some extent in P. vivax is a major problem.
Control measures are eradication of infected anopheline mosquitos.
Vaccines are being developed and tried but none is available ye for routine use.
DRUG CLASSIFICATION

Several classes of antimalarial drugs are available
Table 53-1. Major antimalarial drugs.

Drug Class Use
Chloroquine 4-Aminoquinoline Treatment and chemoprophylaxis of infection with sensitive parasites

Amodiaquine1 4-Aminoquinoline Treatment of infection with some chloroquine-resistant P falciparum strains

Quinine Quinoline methanol Oral treatment of infections with chloroquine-resistant P falciparum

Quinidine Quinoline methanol Intravenous therapy of severe infections with P falciparum

Mefloquine Quinoline methanol Chemoprophylaxis and treatment of infections with P falciparum

Primaquine 8-Aminoquinoline Radical cure and terminal prophylaxis of infections with P vivax and P ovale

Sulfadoxine
-pyrimethamine Folate antagonist combination Treatment of infections with some chloroquine-resistant P falciparum
(Fansidar)

Proguanil1 Folate antagonist Chemoprophylaxis (with chloroquine)

Doxycycline Tetracycline Treatment (with quinine) of infections with P falciparum; chemoprophylaxis

Halofantrine Phenanthrene methanol Treatment of infections with some chloroquine-resistant P falciparum

Artemisinins Sesquiterpene lactone endoperoxides Treatment of infection with multidrug-resistant P falciparum

Atovaquone-proguanil
(Malarone) Quinone-folate antagonist combination Treatment and chemoprophylaxis of P falciparum infection
Structures of the major
drugs.
CHLOROQUINE

Chemistry & Pharmacokinetics

Chloroquine is a synthetic 4-aminoquinoline formulated as the phosphate salt for oral use. It is rapidly and almost
completely absorbed from the gastrointestinal tract, reaches maximum plasma concentrations in about 3 hours, and is
rapidly distributed to the tissues. The complex pharmacokinetics of chloroquine necessitate the use of a loading dose to
rapidly achieve effective serum concentrations . It has a very large apparent volume of distribution of 100-1000 L/kg and is
slowly released from tissues and metabolized. Chloroquine is principally excreted in the urine with an initial half-life of 3-5
days but a much longer terminal elimination half-life of 1-2 months.

Antimalarial Action & Resistance

A. Antimalarial Action: Chloroquine is a highly effective blood schizonticide and remains the principal antimalarial drug in
much of the world. It is also moderately effective against gametocytes of P vivax, P ovale, and P malariae but not against
those of P falciparum. Chloroquine is not active against liver stage parasites.

B. Mechanism of Action: The mechanism of action remains controversial. Chloroquine probably acts by concentrating in
parasite food vacuoles, preventing the polymerization of the hemoglobin breakdown product, heme, into hemozoin and
thus eliciting parasite toxicity due to the buildup of free heme.

C. Resistance: Resistance to chloroquine is now very common among strains of P falciparum and uncommon but
increasing for P vivax.

Clinical Uses

A. Treatment: Chloroquine is the drug of choice for the treatment of nonfalciparum and sensitive falciparum malaria.
B. Chemoprophylaxis: Chloroquine is the preferred chemoprophylactic agent in malarious regions without resistant
falciparum malaria. Eradication of P vivax and P ovale requires a course of primaquine to clear hepatic stages.
C. Amebic Liver Abscess

Adverse Effects : Pruritus is common, primarily in Africans. Nausea, vomiting, abdominal pain, headache, anorexia,
malaise, blurring of vision, and urticaria are uncommon. The long-term administration of high doses of chloroquine for
rheumatologic diseases can result in irreversible ototoxicity, retinopathy, myopathy, and peripheral neuropathy etc.
AMODIAQUINE

Amodiaquine is closely related to chloroquine, and it probably shares mechanisms of action and resistance with that drug.
Amodiaquine has been widely used to treat malaria in many countries because of its low cost, limited toxicity, and, in
some areas, effectiveness against chloroquine-resistant strains of P falciparum.

QUININE & QUINIDINE

Introduction

Quinine and quinidine remain first-line therapies for falciparum malariaspecially severe diseasehough toxicity
concerns complicate therapy. Resistance to quinine is uncommon but increasing.

Antimalarial Action & Resistance

A. Antimalarial Action: Quinine is a rapidly acting, highly effective blood schizonticide against the 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.

B. Resistance: Increasing in vitro resistance of parasites from a number of areas suggests that quinine resistance will be
an increasing problem in the future

Clinical Uses

A. Parenteral Treatment of Severe Falciparum Malaria:
B. Oral Treatment of Falciparum Malaria
C. Malarial Chemoprophylaxis
D. Babesiosis

Adverse Effects : tinnitus, headache, nausea, dizziness, flushing, and visual disturbances, a constellation of symptoms
termed cinchonism. Severe hypotension can follow too-rapid intravenous infusions of quinine or quinidine.
Electrocardiographic abnormalities (QT prolongation) are fairly common with intravenous quinidine. Blackwater fever is a
rare severe illness that includes marked hemolysis and hemoglobinuria in the setting of quinine therapy for malaria.
MEFLOQUINE

Introduction

Mefloquine is effective therapy for many chloroquine-resistant strains of P falciparum and against other species.

Chemistry & Pharmacokinetics

Mefloquine hydrochloride is a synthetic 4-quinoline methanol that is chemically related to quinine.
It can only be given orally because severe local irritation occurs with parenteral use. It is well absorbed, and peak plasma
concentrations are reached in about 18 hours. Mefloquine is highly protein-bound, extensively distributed in tissues, and
eliminated slowly, allowing a single-dose treatment regimen. The terminal elimination half-life is about 20 days, allowing
weekly dosing for chemoprophylaxis. With weekly dosing, steady state drug levels are reached over a number of weeks;
this interval can be shortened to 4 days by beginning a course with three consecutive daily doses of 250 mg, though this is
not standard practice. Mefloquine and acid metabolites of the drug are slowly excreted, mainly in the feces. The drug can
be detected in the blood for months after the completion of therapy.

Antimalarial Action & Resistance

A. Antimalarial Action: Mefloquine has strong blood schizonticidal activity against P falciparum and P vivax, but it is not
active against hepatic stages or gametocytes. The mechanism of action of mefloquine is unknown.

B. Resistance: Sporadic resistance to mefloquine has been reported from many areas. At present, resistance appears to
be uncommon except in regions of Southeast Asia with high rates of multidrug resistance (especially border areas of
Thailand). Mefloquine resistance appears to be associated with resistance to quinine and halofantrine but not with
resistance to chloroquine.

Clinical Uses

A. Chemoprophylaxis
B. Treatment: Mefloquine is effective in treating most falciparum malaria, but the drug has not been approved by the FDA
for this purpose. The drug is not appropriate for treating individuals with severe or complicated malaria since quinine and
quinidine are more rapidly active and drug resistance is less likely with those agents.
PRIMAQUINE

Introduction

Primaquine is the drug of choice for the eradication of dormant liver forms of P vivax and P ovale.

Antimalarial Action & Resistance

A. Antimalarial Action: Primaquine is active against hepatic stages of all human malaria parasites. It is the only available
agent active against the dormant hypnozoite stages of P vivax and P ovale.. Primaquine acts against erythrocytic
stage parasites, but this activity is too weak to play an important role. The mechanism of antimalarial action is
unknown.

B. Resistance: Some strains of P vivax in New Guinea, Southeast Asia, and perhaps Central and South America are
relatively resistant to primaquine. Liver forms of these strains may not be eradicated by a single standard treatment
with primaquine and may require repeated therapy with increased doses (eg, 30 mg base daily for 14 days) for
radical cure.

Clinical Uses

Therapy (Radical Cure) of Acute Vivax and Ovale Malaria
Terminal Prophylaxis of Vivax and Ovale Malaria
C. Chemoprophylaxis of Malaria.
D. Gametocidal Action
E. Pneumocystis carinii Infection.

Adverse Effects : nausea, epigastric pain, abdominal cramps, and headache, and these symptoms are more common
with higher dosages and when the drug is taken on an empty stomach. More serious but rare adverse effects
include leukopenia, agranulocytosis, leukocytosis, and cardiac arrhythmias. Standard doses of primaquine may
cause hemolysis or methemoglobinemia (manifested by cyanosis), especially in persons with G6PD deficiency or
other hereditary metabolic defects.

INHIBITORS OF FOLATE SYNTHESIS

Introduction

Inhibitors of enzymes involved in folate metabolism are used, generally in combination regimens, for the treatment and
prevention of malaria.

Chemistry & Pharmacokinetics

Pyrimethamine is a 2,4-diaminopyrimidine related to trimethoprim
Proguanil is a biguanide derivative

Antimalarial Action & Resistance

A. Antimalarial Action: Pyrimethamine and proguanil act slowly against erythrocytic forms of susceptible strains of all
four human malaria species..

B. Mechanism of Action: Pyrimethamine and proguanil selectively inhibit plasmodial dihydrofolate reductase, a key
enzyme in the pathway for synthesis of folate. Sulfonamides and sulfones inhibit another enzyme in the folate
pathway, dihydropteroate synthase.

C. Resistance: In many areas, resistance to folate antagonists and sulfonamides is common for P falciparum and less
common for P vivax. Resistance is due, at least in part, to mutations in dihydrofolate reductase and dihydropteroate
synthase. Because different mutations may mediate resistance to different agents, cross-resistance is not uniformly
seen.

Clinical Uses

Chemoprophylaxis:
Treatment of Chloroquine-Resistant Falciparum Malaria
C. Presumptive Treatment of Falciparum Malaria
Toxoplasmosis
Pneumocystosis
ANTIBIOTICS

Tetracycline and doxycycline are active against erythrocytic schizonts of all human malaria parasites.
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.
Azithromycin also has antimalarial activity and is now under study as an alternative chemoprophylactic drug.
Antimalarial activity of fluoroquinolones has been demonstrated, but efficacy for the therapy or chemoprophylaxis of
malaria has been suboptimal.

Antibiotics also are active against other protozoans.

ATOVAQUONE

Atovaquone, a hydroxynaphthoquinone was initially developed as an antimalarial but has been approved by the FDA for
the treatment of mild to moderate P carinii pneumonia. The drug is only administered orally.
Atovaquone is an alternative therapy for P carinii infection, though its efficacy is lower than that of trimethoprim-
sulfamethoxazole.

HALOFANTRINE

Halofantrine hydrochloride, a phenanthrene-methanol related to quinine, is effective against erythrocytic stages of all four
human malaria species.
It is not active against hepatic stages or gametocytes.
Halofantrine is rapidly effective against most chloroquine-resistant strains of P falciparum, but its use is limited by irregular
absorption and cardiac toxicity.
In addition, cross-resistance with mefloquine may occur.

ARTEMISININ & ITS DERIVATIVES

Artemisinin (qinghaosu) is a sesquiterpene lactone endoperoxide , Artemisinin and analogs are very rapidly acting blood
schizonticides against all human malaria parasites. Artemisinin has no effect on hepatic stages. Artemisinin-resistant P
falciparum has not yet been identified. The antimalarial activity of artemisinin probably results from the production of free
radicals that follows the iron-catalyzed cleavage of the artemisinin endoperoxide bridge in the parasite food vacuole.