Pharmacology excellent knowledge you need

1. BHM-2221
ANTI-PROTOZOAL
AGENTS Mrs. N Mwila MSc

2. CHEMOTHERAPEUTIC AGENTS
 Application of chemical substances that are 'selectively toxic' to
invading prokaryotic microbes with minimal effects on the host
1. ANTIMICROBIAL AGENTS:
 ANTIBACTERIAL DRUGS
 ANTIFUNGAL DRUGS
 ANTIVIRAL DRUGS
2. ANTI-PARASITIC AGENTS
 ANTIHELMINTHIC DRUGS
 ANTIPROTOZOAL DRUGS
3. ANTICANCER CHEMOTHERAPY.

3. INTRODUCTION

4. PROTOZOA
 Protozoa are unicellular, eukaryotic parasitic organisms
 Parasitic organisms depend on others organisms for their nutrients
 Protozoa cells have metabolic processes closer to the human host than to
the prokaryotic bacterial pathogens
 Hence protozoa diseases are less easily treated compared to bacterial
infections
 Many anti-protozoal drugs cause serious toxic effects in the host,
particularly on cells showing high metabolic activity:
-Neuronal,
-Renal tubules,
-Intestinal and bone marrow

5. PROTOZOA
 Protozoa, fungi and Helminths are eukaryotic parasitic
organisms
 Protozoa cells have metabolic processes closer to the human
host than to the prokaryotic bacterial pathogens
 Less easily treated compared to bacterial infections
WHY???
 Eukaryotic cells are very similar to human cells. Making it more
difficult to develop drugs with selective toxicity

6. PROTOZOA FORMS
 Protozoa are divided into FOUR major groups based on
locomotion /motility characteristics:
1. Flagellates: Giardia, Leishmania, Trichomonas vaginalis, and
Trypanosoma
2. Amoeboid Forms: Entamoeba histolytica
3. Ciliates : Balantidium the largest protozoa that infect
humans/causes large intestinal infections e.g. diarrhea
(balantidiasis, water borne treated with metronidazole or
tetracyclines)

7. PROTOZOA FORMS CONT….
4. Sporozoa ( non-motile move by gliding)
 Plasmodium species
 Toxoplasma
 Cystoisospora belli formerly known as isospora belli
 Cryptosporidium parvum

10. COMMON PROTOZOA INFECTIONS
 Protozoa infections cause tissue damage resulting in disease
 Tissue damage is often due to immune response to the parasite or due to
toxic protozoal products or mechanical tissue damage
INFECTIONS
 Malaria (Plasmodium species affects RBCs)
 Amoebiasis /Amoebic dysentery (Entamoeba histolytica)
 Giardia infections (Enteritis affects the gut)
 Trichomoniasis (Trichomonas vaginalis)
NOTE: some protozoa conditions are opportunistic /associated with low
immune status or being in an area of high risk of infection

11. FLAGELLATED FORMS

12. INFECTIONS BY FLAGELLATED
PROTOZOA FORMS
1. Giardia lamblia
 Enteritis – commonly affects upper GIT (small intestine)due to fecal
contamination of drinking water e.g. common in campers
2. Trichomonas vaginalis – anaerobic flagellate
 urethritis vaginitis - sexually transmitted or contact with vaginal urethral
discharges
 Foul-smelling vaginal discharge ,painful urination in women
 Men have no symptoms

13. FLAGELLATED FORMS CONT…
3. Trypanosoma species
 Its flagilated but also Include nonflagellated forms in its lifecycle.
 Enter wound created by fly bite, enter blood, lymph, eventually CNS.
 Trypanosoma gambiense – causes African sleeping sickness
(Trypanosomiasis) whose vector is a Tsetse fly and reservoirs game animals (
pentamidine)
4. LEISHMANIASIS
 Caused by a protozoa transmitted by a sand-fly found in sandy areas
through a bite when sucking blood ,manifested by skin lesions and ulcers:
treated with Liposomal amphotericin B

14. SPOROZOA FORMS

15. Toxoplasmosis
1. Toxoplasma gondii (Toxoplasmosis)
 This is an intracellular parasite that is found in a wide variety of animals including
birds, mice, cats and humans.
 Toxoplasmosis disease is usually mild to asymptomatic in immunologically
competent adults.
 Causes inflammation to different parts of the body
 Toxoplasmosis can infect lymph nodes, the brain, the eyes, lungs, heart e.tc
 Immunocomprimised patient with AIDS result with severe neurological disease
(differential diagnosis of Cryptococcal meningitis)
 Trophozoites in spinal fluid is one method of diagnosis
 Treatment: Pyrimethamine/Folinic Acid (D.O.C.), Co-trimoxazole, can also be
used

16. Cryptosporidiosis
2. Cryptosporidium parvum
 Common parasite in immune compromised, children, old age, HIV
 Chronic diarrhea in immunocompromised (HIV/AIDS patients)
 Respiratory and gall bladder infections - major cause of death
 Transmitted through fecal oral route mainly water borne
 Resistant to water purification methods – chlorination
 Cryptosporidiosis ( caused by cryptosporidium parvum)
 High incidence of infection among HIV/AIDS patients
 Nitazoxanide is approved by FDA for Cryptosporidiosis therefore ,
Albendazole and co-trimoxazole are alternative

17. Cystoisosporiasis
3. Cystoisosporiasis
 Previously known as isosporiasis (caused by a protozoan cystoisospora belli
formerly known as isospora belli
 Common cause of chronic diarrhea in immunocompromised
(HIV/AIDS patients)
NOTE: Cystoisosporiasis treated with high dose of oral Trimethoprim/
Sulfamethoxazole (co-trimoxazole/Septrin ) TMP-160mg +SMX 800mg bid X10
 Albendanzole 400mg can also be used as an alternative

18. AMOEBOID FORMS

19. ENTAMOEBA HISTOLYTICA
4. Entamoeba histolytica
 Drinking contaminated water and food e.g. salads
 Life cycle divided into two stages: trophozoite active feeding stage, and the
cyst resistant infective stage
 The amoebic trophozoites remain actively motile, feeding on red blood cells,
as long as environmental conditions are favorable.
 Inflammation, hemorrhage, secondary bacterial infection develop
 Ulcers in intestinal mucosa cause amoebic dysentery and anemia.
 May invade peritoneal cavity, invasion of the liver.

20. CHEMOTHERAPY
ANTIPROTOZOAL AGENTS

21. CHEMOTHERAPY OF AMOEBIASIS
 Amoebiasis is an infection of the intestinal tract caused by Entamoeba
histolytica. Amoeba is found in two forms:
1. Cyst form (non-invasive): living in the lumen of the bowel
2. Vegetative form (invasive) or trophozoite: which may penetrate intestinal
wall causing ulceration of mucosa of the large intestine
 Affects the large intestines causing amoebic dysentery (blood diarrhea
)
 May also cause extraintestinal amoebiasis as hepatic or pulmonary
amoebiasis

22. CLASSIFICATION OF ANTI-AMOEBIC DRUGS
1. LUMINAL AMOEBICIDES (against cyst form in the bowel)
I. Nitazoxanide, Diloxanide Furoate,
II. Antibiotics: Tetracycline,
2. TISSUE AMOEBICIDES (against invasive trophozoite
forms in the tissue
I. Nitroimidazoles: Metronidazole(flagyl), Tinidazole,
Seconidazole

23. TISSUE
AMOEBICIDES

24. TISSUE AMOEBICIDES CONT…
1. For both intestinal & extraintestinal amoebiasis:
 Metronidazole,
 Tinidazole,
 Secnidazole,
 Ornidazole,
 Satranidazole
 Emetine, Dihydroemetine
2. For extraintestinal amoebiasis:
 Chloroquine

25. 1. METRONIDAZOLE
Mechanism of action
 Selectively toxic for amoeba, some other protozoa and anaerobic bacteria
(e.g. bacteroides fragilis)
 The nitro group of Metronidazole serves as an electron acceptor forming
reduced cytotoxic compounds that bind to the proteins and DNA of
microbes resulting cell death
 The nitro group is reduced to highly reactive nitro radicals that exerts
cytotoxicity resulting in cell death of the microbes
NOTE: its nitro group is reduced by certain redox proteins operative only in
anaerobic bacteria (hence also used to cover anaerobes)

26. METRONIDAZOLE CONT…….
Antimicrobial Spectrum
 Against E.histolytica, Giardia lamblia, trichomonas vaginalis, anaerobic cocci,
anaerobic gram negative bacilli and gram positive bacilli such as clostridia.
In addition has activity against:
 Anaerobic bacteria, Pseudomembranous colitis due to Cl. Difficile and
Helicobacter pylori e.tc
 Metronidazole is effective against both luminal and systemic forms of
amoebiasis. Often combined with a luminal amoebicide (such as diloxanide
furoate) to provide greater cure rates

27. METRONIDAZOLE………
Uses:
 Amoebiasis: First line drug for all forms of amoebic reactions
kinetics : well absorbed, widely distributed – Excreted in urine T1/2= 8hrs
ADRs:
 Prolonged administration may cause peripheral neuropathy & CNS effects,
Seizures with high doses
 Thrombophlebitis of the injected vein if solution is not well diluted
 Anorexia, nausea, vomiting, epigastric distress, abdominal cramps, metallic
taste, dizziness, vertigo, neuropathy, disulfiram-like effects if taken with
alcohol

28. TINIDAZOLE
 Similar to metronidazole but has a longer half life
 Differs: – Metabolism is slower, t1/2=12hrs
 Duration of action is longer, dosage schedules are simpler
 More suited for single dose, or once twice daily therapy – Better tolerated
 it is more effective and is less teratogenic than metronidazole
 it can be given as a single dose of 2g/day or depending on the type of
infection involved

29. OTHER NITROIMIDAZOLES
1. Secnidazole
 Metabolism slower – T1/2= 17-29hrs
2. Ornidazole: – T1/2= 12-14hrs
3. Satranidazole: – T1/2=14hrs – Better tolerability
 Activity against anerobic bacteria and Pseudomembranous colitis due to Cl.
Dif etc

30. LUMINAL
AMOEBICIDES

31. 1. DILOXANIDE FUROATE
 A luminal active agent used to eradicate the cysts of entamoeba histolytica
 It is a directly acting amoebicide
 It is hydrolyzed in intestinal mucosa into diloxanide and furoic acid
 About 90% of diloxanide is absorbed, conjugated and excreted in urine
 The unabsorbed 10% part is the active amoebicide

32. DILOXANIDE FUROATE CONT..
Side effects:
 flatulence, nausea, abdominal cramps, dry mouth, urticarial
 Highly effective luminal amoebicide
 High curative rates in mild amoebiasis & in asymptomatic cyst passers
 Well tolerated
 Drug of choice for mild intestinal/asymptomatic amoebiasis
 Given after any tissue amoebicide to eradicate cysts

33. 2. Paromomycin
 An aminoglycoside antibiotic
 Only effective against the luminal forms of E. histolytica and tapeworms
since it is not significantly absorbed in the GIT
 It is also used in cryptosporidiosis
MoA:
 inhibits protozoal protein synthesis by binding to the 30s ribosomal RNA in
the aminoacyl-tRNA site causing misreading of mRNA codons
Side Effects:
 GIT upsets e.g. diarrhoea

34. 3. TETRACYCLINES
An Antibiotic
 Have weak direct amoebicidal effect
 Only at high concs reduce proliferation of Entamoeba in the colon
 Anti-malaria effects on Hypnozoites (dormant forms in the liver involved in
the life cycle of malaria parasitic protozoa
 their effects on intestinal bacterial flora make them useful with a luminal
amoebicide in mild to moderate intestinal amoebiasis
 Dose: tetracycline 250mg to 500mg qid x 10/7
 Luminal amoebicide: Not for amoebic acute dysentery
 For hepatic amoebiasis

35. CHEMOTHERAPY
FOR OTHER
PROTOZOAL INFECTIONS

36. DRUGS FOR LEISHMANIA
Visceral Leishmaniasis : (Kala-azar) a black fever caused by infection with
Leishmania donovani
DRUGS
1. Pentavalent antimonials: DOC is Sodium stibogluconate
2. Polyene antifungal: Amphotericin B
3. Diamidine: Pentamidine
3. Other drugs : Miltefosine, Paromomycin, Allopurinol

37. DRUGS FOR TRICHOMONAS
I. Oral / injection
 Metronidazole
II. Intravaginally Drugs:
 Diiodohydroxyquin
 Quiniodochlor
 Clotrimazole

38. DRUGS FOR BALANTIDIUM COLI
(Ciliate Form)
I. Oral / injection: METRONIDAZOLE
II. TETRACYCLINE
III. IODOQUINOL
NOTE: Details about the drug refer to above notes

39. PENTAMIDINE

40. PENTAMIDINE
Pentamidine is an antibiotic active against Leishmania-donovani, Trypanosoma,
Pnemocystis jiroveci,
 Interferes with protein synthesis, DNA replication and aerobic glycolysis
ADRs: Its mechanism contribute to effects on multiple organs resulting in various side
effects
 Allergy due to histamine release : sharp fall in BP, CVS collapse, dyspnea, palpitations,
fainting, vomiting, fever occur frequently after I.V injection
 rashes, mental confusion, kidney, liver damage, ECG changes, cardiac arrhythmias
 Cytolysis of β-cells: Insulin released initially causing hypoglycaemia
 Later can cause permanent insulin dependent Diabetes

41. COMMONLY Drugs USED IN PRACTICE
PROTOZOA: immunocompromised (non bloody)
 Metronidazole:800mg orally 3 times daily for 5 -10 days
 Tinidazole ---- Adult: 2g daily for 2 – 3 days. Child: 50 – 60 mg/kg orally for 3 days.
 Isospora Belli – Co-trimoxazole 960mg / double four times daily orally for 10 – 28
days.
 Cryptosporidium – Albendazole 400mgtwice daily orally for one month also
Nitazoxanide approved by FDA (in non immune compromised ) may help but as the
immunity improve with ART antiretroviral therapy the condition improves.
Bloody diarrhea: Bacterial like dysentery
 Quinolones, Nalidixic acid 500mg qid x 10/7,

42. THE END