1

ANTI-PROTOZOAL DRUGS

Dr.m.Zabihi

2

Protozoal Infections - Introduction•Amebiasis , Giardiasis , Trichomoniasis , Trypanosomiasis , Leishmaniasis

•transmitted by insect vectors or directly from other mammalian

•protozoa multiply rapidly in their hosts•Effective vaccines are unavailable•Chemotherapy is only practical way to both:

1. Treat infected individuals2. Reduce transmission

•immune system plays a crucial role in protecting of protozoal infections

3

Protozoal Infections - Amebiasis•10% of the world's population•Ingested E. histo lytica cysts from contaminated food or water survive acid gastric contents and transform into trophozoites that reside in the large intestine

1. Asymptomatic

2. colitis and bloody diarrhea (amebic dysentery)

3. amebic liver abscess

4

Protozoal Infections - Amebiasis•The cornerstone of therapy :

•nitroimidazole compound Metronidazole or its analogs Tinidazole and ornidazole

• the drugs of choice : Metronidazole and Tinidazole•metronidazole is less effective against cysts • luminal agents to eradicate any E. histolytica trophozoites residing within the gut lumen

•Luminal agents are also used to treat asymptomatic individuals•Paromomycin and Iodoquinol

• two effective luminal agents•Diloxanide furoate

5

Protozoal Infections - Giardiasis•Giardia intestinalis1. An asymptomatic carrier state2. acute self-limited diarrhea3. chronic diarrhea•a 5-day course of metronidazole usually is successful•A single dose of tinidazole probably is superior to metronidazole

•Paromomycin•Furazolidone

6

Protozoal Infections - Trichomoniasis•Trichomonas vaginalis•the genitourinary tract of the human host•Women & Men•The drug of choice : Metronidazole•Tinidazole•better tolerated than metronidazole•successfully at higher doses to treat metronidazole-resistant T. vaginalis

7

Protozoal Infections - Toxoplasmosis•Toxoplasma gondii•The acute illness

•usually self-limiting•treatment rarely is required

•Individuals who are immunocompromised•a risk of developing toxoplasmic encephalitis

•Clinical manifestations of congenital toxoplasmosis vary widely

8

Protozoal Infections - Toxoplasmosis•The primary treatment for toxoplasmic encephalitis

• Pyrimethamine and sulfadiazine• Clindamycin : The substitution of sulfadiazine without loss of efficacy

•Alternative regimens• azithromycin, clarithromycin, atovaquone, or dapsone +• Trimethoprim-sulfamethoxazole or pyrimethamine and folinic acid

•Acute acquired toxoplasmosis in pregnancy : Spiramycin•Fetal infection

• the combination of pyrimethamine, sulfadiazine, and folinic acid is administered to the mother• only after the first 12-14 weeks of pregnancy and to the newborn in the postnatal

period

9

Protozoal Infections - Cryptosporidiosis

•Cryptosporidium parvum (newly named C. hominis)•Diarrhea

•self-limited infection in most individuals•in immunocompromised individuals, the severity of voluminous, secretory diarrhea

•Nitazoxanide •the only drug approved for cryptosporidiosis in the U.S.

10

Protozoal Infections - Trypanosomiasis•African trypanosomiasis, or "sleeping sickness" •Trypanosoma brucei•The parasite is entirely extracellular•stage 1 : early human infection

•Pentamidine for T. brucei gambiense and Suramin for T. brucei rhodesiense

•stage 2 : CNS involvement•Traditionally : Melarsoprol

•a highly toxic agent that causes a fatal reactive encephalopathy in 2-10% of treated patients

•the only alternative : Eflornithine•which was developed originally as an anticancer

11

Protozoal Infections - Leishmaniasis• obligate intramacrophage protozoa• Leishmaniasis increasingly is becoming recognized as an AIDS-associated opportunistic infection• Cutaneous forms of leishmaniasis generally are self-limiting

• with cures occurring in 3-18 months after infection• can leave disfiguring scars

• The mucocutaneous, diffuse cutaneous, and visceral forms of the disease do not resolve without therapy

• The classic therapy for all species of Leishmania• pentavalent antimony

• alternative : amphotericin B• highly effective agent for visceral leishmaniasis• The drug of choice for antimony-resistant disease

• Paromomycin• has been used with success as a parenteral agent for visceral disease• Its topical formulations have efficacy against cutaneous disease

• Pentamidine may also be used for cutaneous disease

12

Protozoal Infections - Other Protozoal Infections

• Babesiosis• mild and self-limiting• severe or even fatal in immunocompromised individuals• combination of clindamycin and quinine for severe disease• combination of azithromycin and atovaquone for mild or moderate infections

• Balantidiasis• an infection of the large intestine• Tetracycline

• Isospora belli• self-limited diarrhea in normal hosts and can cause prolonged diarrhea in individuals

with AIDS• Trimethoprim-sulfamethoxazole

• Microsporidia• Diarrhea in immunocompromised individuals• Albendazole, a benzimidazole derivative and inhibitor of β-tubulin polymerization

13

Anti-Protozoal Drugs•Amphotericin B

•visceral leishmaniasis•highly effective ( cures >90% )• the drug of choice for antimonial-resistant cases

•second-line drug for cutaneous or mucosal leishmaniasis•Diloxanide Furoate•Emetine and Dehydroemetine

•systemic amebicide•Dehydroemetine has similar pharmacological properties but less toxic

•have been replaced by metronidazole, which is as effective and far safer

14

Anti-Protozoal Drugs - 8-Hydroxyquinolines

• A luminal agent to eliminate intestinal colonization with E. histolytica• appropriate doses (never to exceed 2 g/day and duration of therapy not

greater than 20 days in adults)• adverse effects are unusual• The most important toxic reaction : subacute myelo-optic neuropathy

• Peripheral neuropathy • High doses in children with chronic diarrhea : optic atrophy and loss of vision

• paromomycin is preferred as the luminal agent used to treat amebiasis• Iodoquinol is a reasonable alternative• A combination with metronidazole

• amebic colitis or amebic liver abscess• a single agent for asymptomatic E. histolytica

15

Anti-Protozoal Drugs - Metronidazole• active against a wide variety of anaerobic protozoal parasites and anaerobic bacteria

• directly trichomonacidal• potent amebicidal activity against E. histolytica• activity against all anaerobic cocci• both anaerobic gram-negative bacilli

• Bacteroides spp., anaerobic spore-forming gram-positive bacilli

16

Anti-Protozoal Drugs - Metronidazole•oral, intravenous, intravaginal, topical•usually is absorbed completely and promptly after oral intake

•With the exception of the placenta, metronidazole penetrates well into body tissues and fluids•vaginal secretions, seminal fluid, saliva, breast milk, CSF

•The liver is the main site of metabolism

17

Metronidazole - Therapeutic Uses1. cures genital infections with T. vaginalis in both females and males in

>90% of cases•dosage•Tinidazole, which has a longer t1/2 than metronidazole, is also used at a 2-g single dose and appears to provide equivalent or better responses than metronidazole

•metronidazole-resistant strains can be treated successfully by giving a second 2-g dose to both patient and sexual partner

2. all symptomatic forms of amebiasis (choice)•amebic colitis and amebic liver abscess

18

Metronidazole - Therapeutic Uses3. Giardiasis

• tinidazole as a single 2-g dose and is appropriate first-line therapy4. susceptible anaerobic bacteria

• Bacteroides, Clostridium, Fusobacterium, Peptococcus, Peptostreptococcus, Eubacterium, Helicobacter

5. polymicrobial infections with aerobic and anaerobic bacteria6. prophylaxis for colorectal surgery7. a single agent to treat bacterial vaginosis8. in regimens to treat infection with H. pylori 9. primary therapy for Clostridium difficile infection10. Crohn's disease with perianal fistulas

19

Metronidazole - Side effects • The most common : headache, nausea, dry mouth, a metallic taste• Vomiting, diarrhea, abdominal distress• Furry tongue, glossitis, and stomatitis occurring during therapy may be associated with an

exacerbation of candidiasis• neurotoxic effects

• Dizziness, vertigo, and very rarely, encephalopathy, convulsions, incoordination, ataxia• warrant discontinuation of metronidazole• caution in patients with active disease of the CNS because of its potential neurotoxicity• should be withdrawn if numbness or paresthesias of the extremities occur

• Urticaria, flushing, and pruritus are indicative of drug sensitivity that can require withdrawal of metronidazole

• Stevens-Johnson syndrome (toxic epidermal necrolysis) (rare)• Dysuria, cystitis, and a sense of pelvic pressure have been reported• disulfiram-like effect• during the first trimester generally is not advised

• Although it has been taken during all stages of pregnancy with no apparent adverse effects

20

Paromomycin• orally to treat cryptosporidiosis and giardiasis• topical to treat trichomoniasis• parenteral for visceral leishmaniasis• treating intestinal colonization with E. histolytica (choice)• amebic colitis and amebic liver abscess

• combination with metronidazole• asymptomatic E. histolytica intestinal colonization• cutaneous leishmaniasis • visceral leishmaniasis• Oral adverse effects

• rare• abdominal pain and cramping, epigastric pain, nausea and vomiting, steatorrhea,

diarrhea

21

Chemotherapy of Malaria: Introduction•single-celled protozoan parasites of the genus Plasmodium

•Five Plasmodium spp. are known to infect humans:•P. falciparum, P. vivax, P. ovale, P. malariae, P. knowlesi

•P. falciparum and P. vivax cause most of the malarial infections worldwide

•P. falciparum accounts for the majority of the burden of malaria •the most severe disease

22

Biology of Malarial Infection1. the bite of a Plasmodium-infected female anopheline mosquito 2. Plasmodium sporozoites, enter the bloodstream3. sporozoites travel to the liver (Within minutes)4. asexual replication within hepatocytes

• production of liver stage schizonts

5. exoerythrocytic stage • tens of thousands of merozoites are released into the bloodstream and infect red

blood cells6. After the initial exoerythrocytic stage

1. P. falciparum and P. malariae are no longer found in the liver2. P. vivax and P. ovale

• can maintain a quiescent hepatocyte infection as a dormant form of the parasite known as the hypnozoite

• can reinitiate symptomatic disease long after the initial symptoms of malaria are recognized and treated

23

Biology of Malarial Infection• clinical manifestations of malaria : The asexual erythrocytic stages • infections due to P. vivax and P. ovale can produce tertian fever patterns (48

hours)• whereas those due to P. malariae can result in quartan fever (72 hours)• most invading merozoites develop into schizonts• a small proportion become gametocytes

• the form of the parasite that is infective to mosquitoes• Gametocytes are ingested into the mosquito midgut during an infectious

blood meal • transform into gametes that can fertilize to become zygotes

24

25

26

Chloroquine and Hydroxychloroquine•Hydroxychloroquine

•equivalent to chloroquine against P. falciparum malaria

•preferred over chloroquine for treatment of mild rheumatoid arthritis and lupus erythematosus •in the high doses required, it may cause less ocular toxicity

•Care should be taken in G6PD deficiency

27

Chloroquine and Hydroxychloroquine - Therapeutic Uses

•Chloroquine is highly effective against erythrocytic forms of Plasmodium•Choice For P. ovale and P. malariae

•Nonmalarial conditions (Chloroquine and hydroxychloroquine)•Hepatic amebiasis•have anti-inflammatory properties

• clinical efficacy in rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis

• photosensitivity diseases• Such as porphyria cutanea tarda and severe polymorphous light

eruption

28

Chloroquine and Hydroxychloroquine - Toxicity and Side Effects

• Toxic manifestations• Cardiovascular• CNS

• GI upset, headache, visual disturbances, urticarial• hemolysis and blood dyscrasias (rare)• discoloration of nail beds and mucous membranes• High daily doses of chloroquine or hydroxychloroquine

• irreversible retinopathy and ototoxicity• Prolonged therapy with high doses of chloroquine or hydroxychloroquine

• toxic myopathy, cardiopathy, peripheral neuropathy

29

Chloroquine and Hydroxychloroquine - Toxicity and Side Effects

• Precautions and Contraindications• Chloroquine is not recommended in epilepsy or myasthenia gravis• Caution in the advanced liver disease or severe GI, neurological, or blood disorders• chloroquine can cause hemolysis in patients with G6PD deficiency• Chloroquine should not be prescribed for patients with psoriasis or other exfoliative skin

conditions• severe reactions

• should also not be used to treat malaria in patients with porphyria cutanea tarda• the danger of cutaneous reactions

• Most important, chloroquine opposes the action of anticonvulsants• increases the risk of ventricular arrhythmias when co-administered with amiodarone or

halofantrine• increases plasma levels of digoxin and cyclosporine• ophthalmological and neurological evaluations every 3-6 months in long-term and high-

dose therapy