MALARIA

It is protozoal disease caused by Plasmodium species, which

are carried by the female anopheles mosquito

Etiology: Four Plasmodium species are responsible for human
malaria,
P. falciparum,
P. vivax,
P. ovale
P. malariae.

BLOOD AND TISSUE PROTOZOA
Antiprotozoal Drugs
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.

Life cycle of malarial parasite
Three stages
Schizogony
Gametogony
Sporogony

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
P. falciparum:

It has an erythrocytic cycle of 48 hours in humans

It produces malignant tertian malaria-'tertian' because the fever was
believed to recur every third day (actually, it varies), 'malignant' because it
is the most severe form of malaria and can be fatal.

The plasmodium induces, on the infected red cell membrane, receptors for
the adhesion molecules on vascular endothelial cells. These parasitised red
cells then stick to uninfected red cells, forming clusters (rosettes), and also
adhere to and pack the vessels of the microcirculation, interfering with
tissue blood flow and causing organ dysfunction including renal failure and
encephalopathy (cerebral malaria).

It does not have an exoerythrocytic stage, so if the erythrocytic stage is
eradicated, relapses do not occur.
P. vivax
It produces benign tertian malaria-

'Benign' because it is less severe than
falciparum malaria and is rarely fatal.

Exoerythrocytic forms may persist for
years and cause relapses.

P. ovale which has a 48-hour cycle and an
exoerythrocytic stage, is the cause of a rare
form of malaria.

P. malariae has a 72-hour cycle, causes
quartan malaria and has no exoerythrocytic
cycle.

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.

The chill and fever follows a cyclic pattern (paroxysm) with the symptomatic period
lasting 8-12 hours.
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. falciparum: persistent spiking or a daily spasm/convulsion is more
usual.

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
This organism causes sequestration of capillary vasculature in the brain,
gastrointestinal and renal tissues.
Chronic malaria results in splenomegaly, hepatomegaly and nephritic syndromes.

Antimalarial drugs
Cinchona alkaloids: Quinine sulphate, hydrochloride
Acridine derivt.: Mapacrine
Biguanide Deri.: Proguanil, Chlorproguanil
4- aminoquinoline deri.: Chloroquine, amodiaquine,
amopyraquine
8-aminoquinoline: Primaquine, pamaquine,
pentaquine
Diaminopyrimidine deri.: Pyrimethamine

Sulphonamide analogues: Sulphadoxine,
sulphamethapyrazine
4- amino carbinolamines: Mefloquine
Phenanthrene-methanols: Halofentrine
Sesquiterpene der.: Artimisinin, Artemether,
Artesunate, Arteether
Tetracyline:Doxycycline
Napthoquine: Atovaquone
Treatment wise

Treatment wise
Drugs used to treat the acute attack:
Blood schizonticidal agents means act on
erythroctic form
This group of drugs includes quinine and
mefloquine, chloroquine, halofantrine,
sulfones, pyrimethamine and proguanil, as
well as the hydroxynaphthoquinone compound
atovaquone.

Drugs that effect a radical cure:
Tissue schizonticidal agents
Acting on the parasites in the liver
Only the 8-aminoquinolines (e.g. primaquine
and tafenoquine) have this action.
These drugs also destroy gametocytes and thus
reduce the spread of infection
Drugs used for chemoprophylaxis
They block the link between the
exoerythrocytic stage and the erythrocytic
stage, and thus prevent the development of
malarial attacks.
chloroquine, mefloquine, proguanil,
pyrimethamine, dapsone and doxycycline.
They are often used in combinations.
Drugs used to prevent transmission
Some drugs (e.g. primaquine, proguanil and
pyrimethamine) have the additional action of
destroying the gametocytes preventing
transmission by the mosquito and thus
preventing the increase of the human reservoir
Structures of the major
drugs.
CHLOROQUINE

Chemistry

Chloroquine is a synthetic 4-aminoquinoline formulated as the phosphate salt for oral use.
Antimalarial Action & Resistance

A. Antimalarial Action:
Chloroquine is a highly effective blood schizonticide and remains the principal antimalarial drug in
much of the world. I
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.
Resistance appears to result from enhanced efflux of the drug from parasitic vesicles



Pharmacokinetics
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 . I

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.



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
D. It is also used in rhuematoid arthritis
E. Giardiasis, Taeniasis
Chloroquine is considered to be safe for use by pregnant women.
Adverse Effects:
Skin rash, angioneuroticedema, photosensitivity , exfoliated dermatitis
Pruritus is common, primarily in Africans. Nausea, vomiting, abdominal pain, headache, anorexia,
malaise, blurring of vision, and urticaria are uncommon.
Parentral administration produces Convulsion , arrythmia,hypotension, cardiac depression
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 malaria specially severe disease
though 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

Pkinetics:
Quinine is well absorbed and is usually administered orally as a
7-day course, but it can also be given by slow intravenous
infusion for severe P. falciparum infections and in patients who
are vomiting.
The half-life of the drug is 10 hours
It is metabolised in the liver and the metabolites are excreted in
the urine within about 24 hours.


Clinical Uses

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

Adverse Effects :
Tinnitus, headache, nausea, dizziness, flushing, and hearing
visual disturbances, a constellation of symptoms termed
cinchonism.
Severe hypotension and severe CNS disturbances such as delirium
and coma can follow too-rapid intravenous infusions of quinine or
quinidine.
Electrocardiographic abnormalities (QT prolongation- cardiac
dysrhythmias ) 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.
It also produces blood dyscrasias (especially thrombocytopenia)
and hypersensitivity
It also increase insulin release so can cause hypoglycemia


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.
.

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.

PKinetics:
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
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 , Tafequine, etaquine

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.
B. Primaquine acts against erythrocytic stage parasites, but this activity is too weak
to play an important role.
C. 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.
Pharmacokinetic
Primaquine is given orally and is well absorbed.
Its metabolism is rapid, and very little drug is present in the body after 10-12 hours.
The half-life is 3-6 hours
Tafenoquine is broken down much more slowly and therefore has the advantage
that it can be given on a weekly basis


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
Presumptive Treatment of Falciparum Malaria
Toxoplasmosis
Pneumocystosis

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.
T1/2: 4-6 hr and metabolite with 1-2 day

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.


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.