Chapter Antimalarials

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Malaria mala aria bad air

called ague, intermittent fever, marsh fever, and TheFever

an ancient disease, one of the most widespreaddiseases

caused by a Plasmodium parasite

use of quinine for treating malaria

Anopheles gambiae -carrier of causative protozoaaccording to Dr. Ronald Ross

Aedes aegypti transmit yellow fever


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Four species of Malaria Plasmodium falciparum cause approximately 50% of

all malaria.

Plasmodium vivax second most common species,accounting for about 40% of all malaria cases.

Plasmodium malariae only 10% of all malarial cases.

Plasmodium ovale least common species.


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Stages of Parasite that causes

Malaria


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Three potential ways to control malaria Elimination of the vector

Drug therapy

Vaccination


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Two ways to control the mosquito carrier To prevent contact between humans and the insect

Elimination of theAnopheles mosquito

-DDT effective insecticides but has been banned.


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The areas of the world where malaria is endemic are

economically poor and cannot:

(a) afford the newer insecticides

(b) fund and maintain the infrastructure

(c) provide medical facilities, staff, and drugs


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Four Plasmodium species

P. falciparum (malignant tertian, subtertian) doesnot have a secondary schizont (secondaryexoerythrocytic) stage.

P. vivax (benign tertian malaria) not as manymerozoites are produced as with P. falciparum.

P. malariae (quartan malaria) this species has a life

cycle similar to that ofP.vivax. P. ovale (mild tertian malaria) least common of the

four types of malaria and similarly to P.vivax and P.malariae, has long lasting secondary schizont stage.


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Five mutations in humans Sickling disease

glucose-6-phosphate dehydrogenase deficiency

Hemoglobin Cvarious thalassemias

Increased production of nitric oxide (NO)


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History Paul Ehrlich (1854-1915)

- founder of modern medicinal chemistry,

chemotherapy, and molecular pharmacology.- magic bullet concept

- trypan red

- Atoxyl

- Salvarsan

- Suramin

- Prontosil


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Cinchona Alkaloids

Cinchona tree - produces four alkaloids and mostantimalarial drugs are based.

Quinine main treatment for malaria and more toxic; usedfor fevers

- P. falciparum resistant to other agents includingchloroquine. (combination w/ pyrimethamine andsulfadoxine, doxycycline, or mefloquine.

- indicated for nocturnal leg cramps

Quinidine - stereoisomer of quinine ; primary indication iscardiac arrhythmias

Cinchonism is a toxic syndrome. Symptoms start tinnitus,headache, nausea, and disturbed vision.


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4-Aminoquinolones Based on quinine structure. This group is substituted

at the same position 4 as quinine and has anasymmetric carbon equivalent to quinines C-9position.

Mefloquinine only R,S isomer marketed


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8-Aminoquinolones Pamaquine used as the methylene-bis-

hyroxynaphthoate because this salt is low solubility.

Primaquine used to prevent relapses caused byexoerythrocytic forms of the parasites.


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Fixed Combinations One combination inhibits folic acid biosynthesis and

dihydrofolate reductase

Other combination acts on the parasites mitochondriaand its dihydrofolate reductase.

e.g. Sulfadoxine and Pyrimethamine (Fansidar)

-schizonticidal

Atovaquone and Proguanil (Malarone)


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Polycyclic Antimalarial DrugsThree antimalarial drugs have polycyclic ring systems

1. Doxycline

2. Halofantrine3. Aminoacridine


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New antimalarial DrugsArtemisinin Artemisia annua (sweet wormwood)

Fosmidomycin isolated from Streptomyces

fermentation broth.


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Current drugs used to prevent and treat Malaria

Class GenericName

Indications for Malaria OtherIndications

Dosing rangesfor tx andprophylaxis ofMalaria

Cinchona

alkaloids

Quinine Chloroquine resistant P.

falciparum; combinationwith other antimalarials;not indicated forprophylaxis

Nocturnal leg

cramps

Adults: 260-650

mg t.i.d for 6-12daysChildren: 10mg/kgever y 8 hrs. for 5-7days

Quinidine Not indicated for malariain the U.S

Cardiacarrhythmias

Cl G i I di ti f Oth D i


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Class GenericName

Indications forMalaria

OtherIndications


4-

aminoquinolones

Chloroquine Prophylaxis and

treatment ofP.vivax, P malariae,and P. ovalemalaria andsusceptible strainsofP. falciparum

malaria

Extraintestinal

(liver)amebiasis; the ff.indications are notapproved in theU.S:Forms of

hypercalcemiaRhumatoidarthritisSolar urticariaDiscoid andsystemic lupus

Prophylaxis for

children:5mg/kg weeklyup to maximumof 300mg

Prophylaxis for

Adults:300mg weekly

Hydroxychloroquine

RheumatoidarthritisDiscoid andsystemic lupuserythematous

Cl G i N I di ti f Oth D i


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Class Generic Name Indications forMalaria

OtherIndications


Hydroxychloroquine

ff. Indicationsare notapproved in theU.S.Forms ofhypercalcemiaPorphyriacutanea tardaSolar urticaria

Prophylaxis forchildren:5mg/kg weeklyup to maximumadult doseProphylaxis for

Adults:310mg weekly onthe same day

Mefloquine Prophylaxis ofP.falciparum andP.vivax malaria;treatment ofP.

falciparum andP. vivax malaria

None Prophylaxis forchildren:62-250 mgProphylaxis for

Adults:250 mg weeklyfor four weeks

Cl G i N I di ti f Oth D i


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OtherIndications


8-

aminoquinolones

Primaquine Prophylaxis and

treatment ofP.vivax

None Children:

0.5mg/kg perday for 14 days

Adults:26.3mg daily for14 days

FixedCombinations

Sulfadoxine andpyrimethamine

Prophylaxis andtreatment ofchloroquine-resistant P.

falciparum

None Each tab.contains 5oomgsulfadoxine and25mgpyrimethamineChildren:

to tabbased on ageonce or twice

weeklyAdults:1-2 tab. Once or

twice weekly

Class Generic Name Indications for Other Dosing ranges


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OtherIndications


Atovaquone and

proguanil

Prophylaxis and

treatment of P.falciparumresistant tootheranitmalarialdrugs

None Adult tab:

250mgatovaquone and100mg proguanilPediatric tab:62.5mgatovaquone and

25mg proguanil

Adult: 1 adulttab dailyChildren: 1-3pediatric tab assingle dosebased on weight

Treatment:Take as singledose for 3consecutive days



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OtherIndications


Polycyclics Doxycline Prophylaxis

against P.falciparumstrains resistantto chloroquineand sulfadoxine-pyrimethamine

Bacteria

infections

Children:

2mg/kg per dayup to 100 mg/day

Adult: 100mgonce daily

Halofantrine Treatment of P.falciparum andP.vivax malaria

None Adults:500mg every sixhours for 3doses (1,500mg),repeated 7days

laterChildren:250-375mgbased on body

weight; followthe same

schedule asadults



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OtherIndications


Newest drug Artemisinin Appearseffective againstall Plasmodiumspeciesincluding P.

falciparum and

P. vivax

None Not yet specified

Possible newdrug

Fosmidomycinand relatedcompounds

Most reportsspecifyPlasmodiumspecies thatinfect rodents

Othermicroorganismsthat have thenonmevalonatepathway

Not yet specified


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Quiz1 What parasite cause Malaria?

2-5 Four species of Malaria.

6-7 two ways to control mosquito carrier8-10 three ways to control malaria

10-15 drugs for malaria

Chapter Antimalarials

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