1. Phase III Comm. I September 2013
Antiprotozoal Drugs
Phase III Comm. I
September 2013

2. Antiprotozoal Drugs Protozoan Diseases
Amebiasis (Entamoeba histolytica)
Giardiasis (Giardia lambia)
Leishmaniasis (Leishmania species)
Malaria (Plasmodium species)
Pneumocystisis Pneumonia (Pneumocystisis carinii )
Toxoplasmosis (Toxoplasma gondii)
Trichomoniasis (Trichomonas vaginalis)

3. Treatment of Malaria
More than 200 million people worldwide have malaria
More than 1 million people die every year from malaria.
It occurs in tropical and sub-tropical areas especially in Asia, Africa, central and south America.
It occurs in south and south-east Anatolia in Turkey

4. Treatment of Malaria Four species of plasmodium cause human malaria:
Plasmodium falciparum,
P vivax,
P malariae, and
P ovale.
P falciparum is responsible for nearly all serious complications and deaths.
Drug resistance is an important therapeutic problem, most notably with P falciparum.

5. Treatment of Malaria PARASITE LIFE CYCLE
An anopheline mosquito inoculates plasmodium sporozoites to initiate human infection.
Circulating sporozoites rapidly invade liver cells, and exoerythrocytic stage tissue schizonts mature in the liver.
Merozoites are subsequently released from the liver and invade erythrocytes.
Merezoides divide in the erythrocite and rupture the cell (hemolysis). They are disseminated into blood as blood schizonts.
Only erythrocytic parasites cause clinical illness.
Repeated cycles of infection can lead to the infection of many erythrocytes and serious disease.
Some merezoides in the erythrocytes develop into male and female gametocytes.
Gametocytes in the erythrocytes are taken up by mosquitoes, where they develop into infective sporozoites (Sexual stage).

6. Treatment of Malaria
In P falciparum and P malariae infection, only one cycle of liver cell invasion and multiplication occurs, and liver infection ceases spontaneously in less than 4 weeks.
Thus, treatment that eliminates erythrocytic parasites will cure these infections.
In P vivax and P ovale infections, a latent hepatic stage, the hypnozoite, is not eradicated by most drugs, and subsequent relapses can therefore occur after therapy directed against erythrocytic parasites.
Eradication of both erythrocytic and hepatic parasites is required to cure these infections.

7. Treatment of Malaria
Drugs that eliminate developing or latent liver forms are called tissue schizonticides;
those that act on erythrocytic parasites are blood schizonticides; and
those that kill sexual stages and prevent transmission to mosquitoes are gametocides.

8. Treatment of Malaria Tissue schizonticides: Blood schizonticides:
Primaquine
Blood schizonticides:
Chloroquine
Amodiaquine
Mefloquine
Quinine
Quinidine
Halofantrine
Lumefantrine
Gametocides:

9. Chloroquine
the drug of choice for both treatment and chemoprophylaxis of malaria since the 1940s.
but its utility against P falciparum has been seriously compromised by drug resistance.
It remains the drug of choice in the treatment of sensitive P falciparum and other species of human malaria parasites.
a highly effective blood schizonticide.
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.

10. Chloroquine Adverse Effects
usually very well tolerated, even with prolonged use.
Pruritus is common.
Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision, and urticaria are uncommon.
Rare reactions include; hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient persons, impaired hearing, confusion, psychosis, seizures, agranulocytosis, exfoliative dermatitis, alopecia, bleaching of hair, hypotension, and electrocardiographic changes (QRS widening, T wave abnormalities).

11. Primaquine
the drug of choice for the eradication of latent liver forms of P vivax and P ovale.
active against hepatic stages of all human malaria parasites.
It is the only available agent active against the latent hypnozoite stages of P vivax and P ovale.
Primaquine is also gametocidal against the four human malaria species.
activity against erythrocytic stage parasites is too weak to play an important role.
generally well tolerated.
infrequently causes nausea, epigastric pain, abdominal cramps, and headache
More serious but rare adverse effects include leukopenia, agranulocytosis, leukocytosis, and cardiac arrhythmias.
may cause hemolysis or methemoglobinemia (manifested by cyanosis), especially in persons with G6PD deficiency or other hereditary metabolic defects.
Patients should be tested for G6PD deficiency before primaquine is prescribed.
should be avoided in patients with a history of granulocytopenia or methemoglobinemia

12. Quinine and Quinidine
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.
Quinine dihydrochloride or quinidine gluconate is the treatment of choice for severe falciparum malaria (due to its side effects not prefered for the other therapies in malaria)
Therapeutic dosages of quinine and quinidine commonly cause tinnitus, headache, nausea, dizziness, flushing, and visual disturbances, a group of symptoms termed cinchonism.
Blackwater fever is a rare severe illness that includes marked hemolysis and hemoglobinuria in the setting of quinine therapy for malaria.

13. Treatment of malaria.
Clinical Setting
Drug Therapy
Alternative Drugs
Chloroquine-sensitive P falciparum and P malariae infections
Chloroquine phosphate, 1 g, followed by 500 mg at 6, 24, and 48 hours
or-
Chloroquine phosphate, 1 g at 0 and 24 hours, then 0.5 g at 48 hours
P vivax and P ovale infections
Chloroquine (as above), then (if G6PD normal) primaquine, 26.3 mg daily for 14 days

14. plus one of the following-
Treatment of malaria.
Clinical Setting
Drug Therapy
Alternative Drugs
Uncomplicated infections with chloroquine-resistant P falciparum
Quinine sulfate, 650 mg 3 times daily for 3-7 days
Malarone, 4 tablets (total of 1 g atovaquone, 400 mg proguanil) daily for 3 days
plus one of the following-
or-
Doxycycline, 100 mg twice daily for 7 days
Mefloquine, 15 mg/kg once or 750 mg, then 500 mg in 6-8 hours
Clindamycin, 600 mg twice daily for 7 days
Artesunate or artemether, single daily doses of 4 mg/kg on day 0, 2 mg/kg on days 2 and 3, 1 mg/kg on days 4-7
Fansidar, three tablets once
Coartem (coartemether 20 mg, lumefantrine 120 mg), 4 tablets twice daily for 3 days
Severe or complicated infections with P falciparum
Quinidine gluconate, 10 mg/kg IV over 1-2 hours, then 0.02 mg/kg IV/min
Artesunate,3 2.4 mg/kg IV or IM, then 1.2 mg/kg every 12 hours for 1 day, then every day
15 mg/kg IV over 4 hours, then 7.5 mg/kg IV over 4 hours every 8 hours
Artemether, 3.2 mg/kg IM, then 1.6 mg/kg/d IM

15. Major antimalarial drugs.
Class
Use
Chloroquine
4-Aminoquinoline
Treatment and chemoprophylaxis of infection with sensitive parasites
Amodiaquine1
Treatment of infection with some chloroquine-resistant P falciparum strains
Quinine
Quinoline methanol
Oral treatment of infections with chloroquine-resistant P falciparum
Quinidine
Intravenous therapy of severe infections with P falciparum
Mefloquine
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 (Fansidar)
Folate antagonist combination
Treatment of infections with some chloroquine-resistant P falciparum
Atovaquone-proguanil (Malarone)
Quinone-folate antagonist combination
Treatment and chemoprophylaxis of P falciparum infection
Chlorproguanil-dapsone
Treatment of multidrug-resistant P falciparum in Africa
Proguanil1
Folate antagonist
Chemoprophylaxis (with chloroquine)
Doxycycline
Tetracycline
Treatment (with quinine) of infections with P falciparum; chemoprophylaxis
Halofantrine1
Phenanthrene methanol
Lumefantrine1
Amyl alcohol
Treatment of P falciparum malaria in fixed combination with artemether (Coartem)
Artemisinins1
Sesquiterpene lactone endoperoxides
Treatment of infection with multidrug-resistant P falciparum
1Not available in the USA.

16. Amebiasis Is the infection with Entamoeba histolytica.
Asymptomatic intestinal infection
Mild to moderate colitis
Dysentery (severe intestinal colitis)
Liver abcess

17. Amebiasis Asymptomatic intestinal infection
Diloxanide furoate is the drog of choice.
500 mg 3 tid., for 10 days.
Eradicates carriage in about %.
Mild to moderate colitis and dysantery
Metronidazole is the drug of choice.
Oral 750 mg tid., for 10 days.
or IV 500 mg every 6 hours.
Plus, Diloxanide furoate or Tetracyclin or Erythromycin

18. Amebiasis Liver Abcess and other exrtaintestinal infections
Metronidazole is the drug of choice.
Oral 750 mg tid., for 10 days.
or IV 500 mg every 6 hours.

19. Metronidazole Good oral absorption
Good tissue distribution including intracellular compartment
Half life is 7,5 hours
Excreted by urine
Specifically reduced in protozoans and converted into toxic reactive reduction products.
Side effects; nausia, headache, dry mouth, mettalic taste.
Contrindicated in pregnancy.

20. Metronidazole Drug of choice in;
E histolytica infections (luminal amebicide should be added i.e. diloxanide furoate, iodoquinol, or paromomycin)
Giardiasis
Trichomoniasis

21. Organism or Clinical Setting
Treatment of other protozoal infections.
Organism or Clinical Setting
Drugs of Choice1
Alternative Drugs
Giardia lamblia
Metronidazole, 250 mg 3 times daily for 5 days
Furazolidone, 100 mg 4 times daily for 7 days
or-
Tinidazole, 2 g once
Albendazole, 400 mg daily for 5 days
Pneumocystis jiroveci, P carinii4
Trimethoprim-sulfamethoxazole, mg trimethoprim component/kg/d IV, or two double-strength tablets every 8 hours for 21 days
Pentamidine
Trimethoprim-dapsone
Clindamycin plus primaquine
Atovaquone
Toxoplasma gondii
Acute, congenital, immunocompromised
Pyrimethamine plus clindamycin plus folinic acid
Pyrimethamine plus sulfadiazine plus folinic acid
Pregnancy
Spiramycin, 3 g daily until delivery
Trichomonas vaginalis
Metronidazole, 2 g once or 250 mg 3 times daily for 7 days