Amodiaquine
Amodiaquine is a 4-aminoquinolone anti-malarial drug similar in structure
and mechanism of action to Chloroquine. It is most frequently used in
combination with Chloroquine, but is also very effective when used alone. It is
thought to be more effective in clearing parasites in uncomplicated malarial
than Chloroquine, thus leading to a faster rate of recovery. However, some fatal
adverse effects of the drug were noted during the 1980�s, thus reducing its
usage in chemoprophylaxis. The WHO�s most recent advice on the subject still
maintains that the drug should be used when the potential risk of not treating
an infection outweighs the risk of developing side effects. It has also been
suggested that it is particularly effective, and less toxic than other
combination treatments in
HIV positive patients.
The drug should be given in doses between 25mg/kg and 35mg/kg over 3 days in
a similar method to that used in Chloroquine administration. Adverse reactions
are generally similar in severity and type to that seen in Chloroquine
treatment. In addition,
bradycardia, itching, nausea, vomiting and some abdominal pain have been
recorded. Some blood and
hepatic disorders have also been seen in a small number of patients.
Pyrimethamine
Pyrimethamine is used in the treatment of uncomplicated malaria. It is
particularly useful in cases of chloroquine-resistant P. Falciparum
strains when combined with
Sulphadoxine. It acts by inhibiting
dihydrofolate reductase in the parasite thus preventing the biosynthesis of
urines and
yrimidines.
Therefore halting the processes of
NA
synthesis,
ell
division and reproduction. It acts primarily on the schizonts during the
hepatic and erythrocytic phases.
Sulphadoxine
The action of
Sulphadoxine is focused on inhibiting the use of
para-aminobenzoic acid during the synthesis of
dihydropteroic acid. When combined with
Pyrimethamine the two key stages in DNA synthesis in the plasmodia are
prevented. It also acts on the schizonts during the hepatic and erythrocytic
phases. It is mainly used for treating P. falciparum infections and is
less active against other Plasmodium strains. However usage is restricted
due to the long half life of the combination which exerts a potentially large
selection pressure on the parasite hence encouraging the possibility of
resistance developing. This combination is not recommended for chemoprophylaxis
because of the severe skin reactions commonly experienced. However it is used
frequently for clinical episodes of the disease.
Proguanil
roguanil
(Chloroguanadine) is a
iguanide;
a synthetic derivative of pyrimidine. It was developed in 1945 by a British
Antimalarial research group. It has many mechanisms of action but primarily is
mediated through conversion to the active
metabolite
cycloguanil pamoate. This inhibits the malarial dihydrofolate reductase
enzyme. Its most prominent effect is on the primary tissue stages of P.
falciparum, P. vivax and P. ovale. It has no known effect against
hypnozoites therefore is not used in the prevention of relapse. It has a
week blood schizonticidal activity, although not recommended for therapy
currently, when combined with
tovaquone
(a
hydroxynaphthoquinone) it has been shown to be effective against multi-drug
resistant strains of P. falciparum. Proguanil is used as a prophylactic
treatment in combination with another drug, most frequently Chloroquine. 3mg/kg
is the advised dosage per day, (hence approximate adult dosage is 200mg). The
pharmacokinetic profile of the drugs indicates that a half dose, twice daily
maintains the
plasma levels with a greater level of consistency, thus giving a greater
level of protection. It should be noted that the Proguanil- Chloroquine
combination does not provide effective protection against resistant strains of
P. falciparum. There are very few side effects to Proguanil, with slight
hair loss and mouth ulcers being occasionally reported following prophylactic
use.
Mefloquine
Mefloquine was developed during the
ietnam
War and is chemically related to quinine. It was developed to protect
American troops against
multi-drug resistant P. falciparum. It is a very potent blood
schizonticide with a long
alf-life.
It is thought to act by forming toxic heme complexes that damage parasitic food
vacuoles. It is now used solely for the prevention of resistant strains of P.
falciparum despite being effective against P. vivax, P. ovale and
P. marlariae. Mefloquine is effective in prophylaxis and for acute therapy.
It is now strictly used for resistant strains (and is usually combined with
rtesunate).
Chloroquine/Proguanil or sufha drug-pyrimethamine combinations should be used in
all other Plasmodia infections.
The major commercial manufacturer of mefloquine-based malaria treatment is
Roche Pharmaceuticals, which markets the drug under the trade name "Lariam".
A dose of 15-25mg/kg is recommended, depending on the prevalence of
Mefloquine resistance. The increased dosage is associated with a much greater
level of intolerance, most noticeably in young children; with the drug inducing
vomiting and
oesophagitis. The effects during pregnancy are unknown, although it has been
linked with an increased number of
tillbirths.
It is not recommended for use during the first trimester, although considered
safe during the second and third trimesters. Mefloquine frequently produces side
effects, including nausea, vomiting, diarrhea, abdominal pain and dizziness.
Several associations with neurological events have been made, namely
affective and
anxiety disorders, hallucinations, sleep disturbances,
sychosis,
toxic encephalopathy, convulsions and
elirium.
Cardiovascular effects have been recorded with bradycardia and
sinus arrhythmia being consistently recorded in 68% of patients treated with
Mefloquine (in one hospital-based study).
Halofantrine
Halofantrine is a relatively new drug developed by the
Walter Reed Army Institute of Research in the 1960s. It is a
phenanthrene methanol, chemically related to Quinine and acts acting as a
blood schizonticide effective against all plasmodium parasites. Its mechanism of
action is similar to other anti-malarials. Cytotoxic complexes are formed with
ferritoporphyrin XI that cause plasmodial membrane damage. Despite being
effective against drug resistant parasites, Halofantrine is not commonly used in
the treatment (prophylactic or therapeutic) of malaria due to its high cost. It
has very variable bioavailability and has been shown to have potentially high
levels of
cardiotoxicity. It is still a useful drug and can be used in patients that
are known to be free of heart disease and are suffering from severe and
resistant forms of acute malaria. The level of governmental control and the
prescription-only basis on which it can be used contributes to the cost, thus
Halofantrine is not frequently used.
A dose of 8 mg/kg of Halofantrine is advised to be given in three doses at
six hour intervals for the duration of the clinical episode. It is not
recommended for children under 10 kg despite data supporting the use and
demonstrating that it is well tolerated. The most frequently experienced
side-effects include nausea, abdominal pain, diarrhoea, and itch. Severe
ventricular dysrhythmias, occasionally causing death are seen when high
doses are administered. This is due to
prolongation of the QTc interval. Halofantrine is not recommended for use in
pregnancy and lactation, in small children, or in patients that have taken
Mefloquine previously.
Lumefantrine is a relative of halofantrine that is used in some combination
antimalarial regimens.
Primaquine
Primaquine is a highly active 8-aminoquinolone that is used in treating all
types of malaria infection. It is most effective against gametocytes but also
acts on hypnozoites, blood schizonticytes and the dormant plasmodia in P.
vivax and P. ovale. It is the only known drug to cure both relapsing
malaria infections and acute cases. The mechanism of action is not fully
understood but it is thought to mediate some effect through creating oxygen
free radicals that interfere with the plasmodial
electron transport chain during
respiration.
For the prevention of relapse in P. vivax and P. ovale 0.15
mg/kg should be given for 14 days. As a gametocytocidal drug in P. falciparum
infections a single dose of 0.75mg/kg repeated 7 days later is sufficient. This
treatment method is only used in conjunction with another effective blood
schizonticidal drug. There are few significant side effects although is has been
shown that Primaquine may cause
norexia,
nausea, vomiting, cramps, chest weakness,
anaemia, some suppression of
yeloid
activity and abdominal pains. In cases of over-dosage
granulocytopenia may occur.
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