Tuesday, 28 June 2016

Anti Malarial

Malaria is spread by the transmission of the parasite, Plasmodium by the female anopheles mosquito.
There are five species;
P. falciparum- The most dangerous of the four, causes high fevers, orthostatic hypotension,
massive erythrocytosis, can ultimately lead to capillary obstruction and death. Doesnt
have an exoerythrocytic cycle, hence if the erythrocytic stage is eradicated the relapse
doesnt occur.
P. vivax Causes a milder form of malaria.
P. malariae common in the tropics and causes quartan malaria with no exoerythrocytic
cycle.
P. ovale rearely found.
P. knowlessi
Lifecycle

Injection of the Plasmodium sporozoites into the blood, which then migrate to the liver
and enter hepatocellular cells, where they undergo the pre-erythrocytic stage of
development and multiplications for the next 10 - 14 days. After this period, the
parasitized cells rupture releasing merozoites.
Upon release, the merozoites invade the RBCs, transform into trophozoites, these utilize
the hemoglobin as a nutrient and become merozoites. This is the erythrocytic stage.
During the period within the RBC, they remodel by adding proteins and phospholipids
onto the RBC membrane; and transfers the Hb in to its food vacuoles. Large amounts of
soluble haem can also be released in the process of concentrating Hb into the food

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vacuoles, this is harmful to the parasite and can be
over come by the polymerization of the haem to
haemozoin by haem polymerase.
The merozoites accumulate leading to rupture of
the RBC, these merozoites then infect another RBC.
Also, these released merozoites can form gametocytes
becoming sporozoites and then can be retaken by a
mosquito.
In P. vivax and P. ovale infections, there is a
dormant stage in the liver called hypnozoite.

Drug Classification.
Its based on the following criteria;
o Tissue schizonticide - Those that eliminate
developing or dormant liver forms.
o Blood schizonticide act on erythrocytic
parasites.
o Gametocides act on the sexual stages and
prevent transmission to the mosquitoes.
None of these agents can provide a radical cure
i.e. elimination of both the hepatic and
erythrocytic stages.
Drugs used to treat the acute attack of
malaria act on the parasites in the blood; they can
cure infections with parasites (e.g. P. falciparum)
that have no exoerythrocytic stage. These are
blood schizonticide, these drugs include;
artemesinin (used in combination with other
drugs),
quinolone-methanols (e.g. quinine and
mefloquine) and various 4-aminoquinolines (e.g.
chloroquin)
anti-folate (e.g. dapsone that inhibits the folate
synthesis and pyrimethamine and proguanil that
inhibit the action of folate)
atovaquone that affects mitochondrial function.
Drugs used for chemoprophylaxis act on
merozoites emerging from liver cells. They block
the link between the exoerythrocytic stage and the
erythrocytic stage. Drugs used in this category are
similar to those used for acute attacks of malaria including lumefantrine.
Drugs used for radical cure are active against parasites in the liver. Tissue schizonticide agents do
this by eradicating the P. ovale and P. vivax parasites in the liver. The 8-aminoquinolones have
this action i.e. primaquine and tafenoquine. They also reduce the spread of infection by killing the
gametocytes.

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Some drugs act on gametocytes and prevent transmission by the mosquito.
The currently available antimalarial agents target four physiologic pathways in plasmodia: heme
metabolism (chloroquine, quinine, mefloquine, and artemisinin), electron transport (primaquine and
atovaquone), protein translation (doxycycline, tetracycline, and clindamycin), and folate metabolism
(sulfadoxine-pyrimethamine and proguanil).

Inhibitors of Haem metabolism.

A. Chloroquine.
Is a synthetic 4-aminoquinolone formulated as a phosphate salt for oral use.
Is a blood schizonticide, that is effective against all the erythrocytic forms of the plasmodium but
not the sporozoites, hypnozoites or gametocyte. Is also effective against extra-intestinal amebiasis
also rheumatoid arthritis and discoid lupus erythromatosus.
At a neutral pH it is uncharged hence can enter the cell but at acidic condition, it becomes
protonated and cant exit the cell.
Mechanism of action It binds to haem, and prevents the polymerization to haemozoin, this leads
to accumulation of haem leading to oxidative stress and rupture of the parasite and the RBC.
(check the fig above for more info. Source: Principles of Pharmacology, the pathophysiology of
drug therapy by Golan page 631)
Pharmacokinetics Is completely absorbed following oral absorption. Severe anemia may be
treated by frequent IM or subcutaneous injection of small doses or slow continuous IV infusion.
Has a large volume of distribution and is concentrated mainly in the
RBCs, liver, kidney, spleen, leukocytes and melanin producing cells.
Chloroquine is dealkylated by the mixed function oxidase system.
Is excreted in the urine and the excretion can be enhanced by acidifying
the urine.
Adverse effects. - GI disturbance, pruritis, headache, blurred vision.

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Contraindication Psoriasis, porphyria, patients with hepatic dysfunction and patients with
neurologic or blood disorders. Shouldnt be given to patients with visual field abnormalities and
myopathy.
Resistance Mutations in the putative transporter PfCRT.
Uses Treatment choice for non-falciparum and sensitive falciparum malaria.
Chemoprophylaxis
Amebic liver disease.
B. Quinine and Quinidine.
This methanol quinolone is obtained from the plant cinchona bark. It is a blood schizonticide that
is active against all the erythrocytic phases of the plasmodium but has no effect on the
exoerythrocytic and the gametocyte of P. falciparum.
Quinine is an alkaloid that consists of a quinolone ring linked by a secondary carbinol to a
quinuclidine ring. Quinidine is an optical isomer to quinine. Is a blood schizonticide.
Mode of action It has a similar mode of action to that of Chloroquine however, it doesnt concentrate
itself in the plasmodium.
Pharmacokinetics Is taken orally and is well distributed in the body. Can also be taken by IV in
patients with severe P. falciparum infection and patients who are vomiting. Is metabolized in the liver
and the metabolites are excreted in the urine.
Contraindications and caution
Shouldnt be given by bolus IV injection due to a risk of cardiac arrhythmias.
Increase the levels of warfarin and digoxin.
Shouldnt be taken with antacids.
Should be avoided in persons with visual and auditory problems.
Patients with severe cinchonism, hemolysis or hypersensitivity.
Pregnant mothers
Adverse effects.
Cinchonism characterized by nausea, tinnitus, vertigo and vomiting.
If the levels in the serum are very high, can lead to hypotension, delirium and also coma.
Thrombocytopenia, agranulocytosis, and leukopenia.
Can cause insulin release.
Black water fever, an acute hemolytic anemia is associated with renal insufficiency.
Hypersensitivity.
Thrombophlebitis.
Clinical uses.
o Treatment of complicated and uncomplicated cases of Falciparum malaria.
o Used in the treatment of Babesiosis.
NB. Is usually given in combination therapy with;
- Pyrimethamine, a folate inhibitor and a slow blood schizonticide.

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- Sulfadoxime
- Dapson
C. Mefloquine.
Is effective against the Chloroquine Resistant P. falciparum and P. vivax. It is used in
combination with Pyrimethamine.
The mode of resistance towards is the same as that of quinine i.e. utilization of efflux pumps.
Pharmacokinetics.
Is taken orally coz of issues with severe irritation with IV admin. Is also well absorbed in the
body.
There is extensive distribution in the body. Also is extensively metabolized in the liver where its
mostly concentrated.
Is eliminated very slowly from the body with a half life of about 20 days hence can be given
prophylactically on a weekly basis. Its excreted mainly in the faeces.
Adverse effects.
GI disturbances, dizziness, abdominal pain. Seizures, depression and acute psychosis.
Contraindications.
- Patients with history of epilepsy, arrhythmias, cardiac conduction defects or sensitivity to the
drug.
- Pregnant mothers or mothers expecting pregnancy.
Uses.
- Used in the treatment of Falciparum malaria.
- Can be used prophylactically.
D. Artemisinin.
- This drug is a sesquiterpene lactone endoperoxide obtained from qing hao (Artemisia annua) also called
sweet worm wood.
- Artemisinin is insoluble and is not given orally but parenterally, other analogues that have been
developed are artemether, artether, dihydroartemisinin and artesunate.
- They are very potent drugs used in the treatment of Plasmodium falciparum reactions and also the
asexual erythrocytic stages of P.vivax.
Mechanism of action.
- This is carried out by the production of free radicals within the plasmodium food vacuole after the
cleavage of the drugs endoperoxide bridge by the heme iron in the parasitised RBCs.
Pharmacokinetics.
- The semisynthetic artemisinins have been formulated for oral (dihydroartemisinin, artesunate, and
artemether), intramuscular (artesunate and artemether), intravenous (artesunate), and rectal
(artesunate) routes.
- They are rapidly absorbed after oral absorption. Artemisinin, artesunate and artemether are rapidly
metabolised to the active form i.e. dihydroartemisinin. They are excreted in bile.
Adverse effects.

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- Nausea, vomiting and diarrhoea as well as dizziness. In high doses, it causes neurotoxicity and a
prolonged QT interval.
Clinical uses.
- Is used in the combination therapy for the chloroquine resistance they include, artemether - lumafantrin
(COARTEM), artesunate - mefloquine and dihydroartemisinin - piperazine.
NB. Lumafantrine is never used alone and its mode of action is preventing the parasitic detoxification of
heme.

Inhibitors of electron transport.

Primaquine
- Is a synthetic 8-aminoquinolone. Is a drug of choice for the eradication of dormant forms of P. vivax
and P.ovale.
- Is the only anti-malarial drug that acts against the exoerythrocytic stage of the malarial parasite. Is
also gametocidal and is effective against all the species. It acts on the hepatic stages of the parasite
and prevents relapse from occurring.
Mode of action
Its not that well understood however, it could be due to a metabolite of
primaquine, quinone that interferes with the functioning of ubiquinone an electron
carrier in the electron transport chain. Another mechanism could be the
metabolites that cause non specific damage to the parasite mitochondrion.
Pharmacokinetics.
-Administration and absorption Is taken orally and is adsorbed well in the body.
-Distribution Is well distributed in the tissues.
-Metabolism Is rapidly metabolized primarily the de-aminated drug
-Elimination and excretion Is excreted in the urine.
Adverse effects
- Nausea, headache, abdominal cramps
-Leukopenia, agranulocytosis and cardiac arrhythmia.
Clinical uses.
- Radical cure of Acute P. ovale and P. vivax infections.
-Chemoprophylaxis of malaria.
-terminal prophylaxis of P.vivax and ovale infections.
-Treatment of P.jiroveci infections.
- Gametocidal action which prevents the transmission of the malarial parasites.
Contraindications and caution
-Shouldn't be given to patients with a history of granulocytopenia .
-Shouldn't be given by IV, the reason is it causes a marked hypotension.
-GP6D deficiency patients.
-Pregnant mothers shouldn't be given coz the foetus is GP6D deficient and hence can cause haemolytic
anaemia.

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Atovoquone.

Is a hydroxynaphthoquinone whose mechanism of action involves the inhibition of

mitochondrial electron transport chain in the protozoa. It carries out this action by mimicking
ubiquinone. It hence prevents ATP synthesis and also prevents pyrimidine synthesis.
Is used prophylactically in the treatment of malaria and treat cases of parasites resistant to
drugs.
Is used synergistically with an anti-folate such as proguanil. This combination should be taken
with food to enhance absorption.
Is administered orally and is excreted from the body unchanged in the faeces.
Is also used in the treatment of infection by P. jiroveci as well as Toxoplasma.
Adverse effects include nausea, diarrhoea, vomiting and rash.

Inhibitors of folate metabolism.

These include pyrimethamine and proguanil which are well absorbed from the GI but
slowly.

Fansidar, is a combination of two drugs sulfadoxime and pyrimethamine is well

absorbed.

Pyrimethamine is extensively metabolised in the liver, and proguanil is converted to

the triazine metabolite cycloguanil, which is active.

Acts slowly on the erythrocytic forms of all the malarial species, they selectively inhibit
the dihydrofolate dehydrogenase enzyme. Resistance is as a result of mutation in the
dihydrofolate dehydrogenase enzyme as well as dihydropteroate synthase enzyme.

Clinical uses.
- Chemoprophylaxis - Pneumocytosis causes by P. jiroveci.
- Treatment of chloroquine resistant - Intermittent preventive therapy - i.e.
malaria treatment given in high risk areas
devoid of the infection status.
- Toxoplasmosis
Adverse effects
- Nausea
- vomiting
- anorexia.
- Rarely it causes Stevens Johnson
syndrome