Antiprotozoal Drugs: Mechanisms, Use & Action (PDF)

13 ANTIPROTOZOAN DRUGS Protozoa are a diverse group of unicellular eukaryotic organisms. These parasites requires intermediate host and definitive host to complete their life cycle. Some species are all able to form cysts , or protective coatings, which allow them to survive outside a...

13 ANTIPROTOZOAN DRUGS Protozoa are a diverse group of unicellular eukaryotic organisms. These parasites requires intermediate host and definitive host to complete their life cycle. Some species are all able to form cysts , or protective coatings, which allow them to survive outside a host for extended periods of time. Numerous chemotherapeutic agents known to possess activity against parasitic protozoa. They have narrow spectrum of activity, but high selective toxicity to protozoan parasites. Thus it is important for you to be familiar which agents will be effective against a particular protozoan parasite. In this module you will LEARNING OBJECTIVES MECHANISMS OF ACTION OF PROTOZOAL DRUGS Antiprotozoal drugs are classified based on their mechanisms of action which are given in Table 1 below. It can be noted in the table that many of the antiprotozoan drugs particularly interfere in the production of energy by the protozoa. Also, some of the antibacterial groups that we have already discussed have antiprotozoal activities whose mechanism of action fall into the other four mechanisms of action presented in the table. The specific antibacterials and their spectrum of activity is summarized in Table 2. Drugs Interfering With Drugs that Drugs that Drugs Drugs that Energy Metabolism interfere with interfere with that interfere with DNA synthesis protein disrupt synthesis of co synthesis cell factors membra ne A. Arsenicals Nitrofurans Lincosami Carboxyli Amprolium 1. Tryparsamid Nitroimidazole des c Sulfonamides e Azalides ionophor diaminepyrimidi 2. Melarsoprol Tetracycli es nes B. Antimonials nes 1. Pentostam 2. Suramin 3. Robenidine C. 8-Hydroxyquinolones 1. Diiodohydro xyquin 2. Iodochlorhy droxyquin D. 4-Hydroxyquinolones 1. Buquinolate 2. Decoquinate 3.Methylbenzoate E. Naphthoquinones 1. Menoctone 2. Ubiquinone F. 8-Aminoquinolines 1. Primaquine Table 2.Antibacterials with antiprotozoal activity. Cryptosporidiosis Coccidiosis Giardiasis/amoebiasis/ Toxoplasmosis Babesiosis Leukoctozoonosis Leishmaniasis Hepatozoonosis Neosporosis Trichomoniasis Trypanosomiasis balantidium Tetracycline Doxycyline Lincosamides: (lincomycin clindamycin Sulfoonamides : Sulfanilamide Sulfaquinoxaline Sulfadimethoxine Ethopabate Sulfamonomethoxine 4- Diaminopyrimidines: Diaverdine Ormethoprim Pyrimethamine 5- Nitrofurans: Nifurtimox Nitrofurazone Furazolidone 2- Nitroimidazoles: metronidazole, tinidazole, ronidazole, dimetridazole, ornidazole, carnidazole, benznidazole,ipronidazole, secnidazole Azalides Azithromycin Aminoglycoside: Paromomycin Polyether Ionophores: Monensin Lasalocid Salinomycin Narasin Maduromicin Semduramicin  POLYETHER IONOPHORES The polyether ionophores were discussed under the antibacterials but they are commonly used as anticoccidia. These group includes: Monensin Lasalocid Salinomycin Narasin Maduromicin Semduramicin MECHANISM OF ACTION Polyether ionophores interfere with the natural ion transport systems of both prokaryotic and eukaryotic cells. They lower the energy barrier necessary for the transmembrane transport of ions and catalyze an electroneutral cation-proton exchange across the barrier. Consequently, they abolish the gradients of Ca 2+, Mg2+, K+, and Na+, causing cell death. CLINICAL USE - Treatment of coccidiosis in poultry (broiler) - These drugs inhibit the development of the first generation schizonts thereby disrupting the first sexual cycle - They may retard the development of the body immunity to coccidia CONTRAINDICATIONS The ionophores are not to be given to or: - layers - horses and other equines - must not be used together with other coccidiostats - fatal when used in therapeutic levels with pleuromutilins NITROIMIDAZOLES The nitroimidazoles are known for their activity against anaerobic bacterias but they are also known antiprotozoal agents. Included in this group are: Metronidazole Tinidazole Ronidazole Dimetridazole Ornidazole, Carnidazole Benznidazol Ipronidazole Secnidazole MECHANISM OF ACTION Nitroimidazoles interfere with nucleic acid synthesis by binding to DNA after appropriate metabolism. The protozoal toxicity is due to short-lived intermediates or free radicals that produce damage by interacting with DNA and possibly other molecules. SPECTRUM Giardia lamblia, Balantidium coli, Entamoeba histolytica, Tritrichomonas foetus, Pentatrichomonas hominis, Trichomonas gallinae, Histomonas maleagridis, Trypanosomas spp. Benznidazole (Radanil)- is specifically for treatment of Chagas disease After presenting the antibacterial drugs that have anti protozoal activity , we now take a look at the bigger group of drugs that works as antiprotozoal by interfering with protozoas’ energy metabolism, Drugs interfering with nucleic acid synthesis and protein synthesis. DRUGS INTERFERING WITH ENERGY METABOLISM OF PROTOZOAS ARSENICALS a.Tryparsamide MECHANISM OF ACTION (MOA): b.Melarsoprol Arsenicals specifically inhibit the enzyme pyruvate kinase of the trypanosomes by reacting with the sulfhydryl (-SH) groups of the enzyme. CLINICAL USE - Treatment for Trypanosomiasis (African Sleeping sickness) in humans - Melarsoprol is more commonly used than Tryparsamide ADVERSE EFFECTS Tryparsamide- Blindness Melarsoprol- encephalopathy, abdominal colic and vomiting ANTIMONIALS a.Pentostan MOA: Interacts with the sulfhydryl group of glycolytic enzymes – phosphofructokinase INDICATION Leishmaniasis b.Suramin MOA: inhibit L-alpha glycero-phosphate oxidase of African trypanosomes INDICATION - Treatment for trypanosomiasis - Less useful as prophylactic agent for T. evansi,T.brucei,T.  equinum and T. equiperdum - Synergistic potentiator of Phentaridines and aminoquinaldine derivatives PENTAVALENT ANTIMONIALS MOA: a.Sodium stibogluconate Inhibit enzymes involved in the synthesis of nucleotides and b.Meglumine inhibit phosphofructokinases, enzymes necessary for glycolytic antimonate and fatty acid oxidation INDICATION Canine leishmaniasis HYDROXYQUINOLONES AND NAPTHOQUINONES SPECTRUM: Coccidia, Babesia sp., Hepatozoon americanum, a.Decoquinate Theileria sp., Cytauxzoon sp., T. gondii, Eimeria sp., malaria, b.Atovaquone Pneumocystis carnii c.Parvaquone, d.Buparvaquone MOA: Block the respiratory chain phosphorylation at a point near the cytochrome B INDICATIONS: Broad spectrum anticoccidials - Antitropozoite - Arrest sporozoite development but do not kill, development may recommence when the drug is withdrawn too early  NAPHTHOQUINONES MOA: a.Menoctone Block the electron transport down the respiratory chain by b.Ubiquinone acting as analogues of Coenzyme Q and cause swelling of mitochondria. CLINICAL USE: - Used as anti- malarial drugs 8-AMINOQUINOLINES a. Primaquine MOA: same as Naphthoquinones CLINICAL USE: -antimalarial drug 8-HYDROXYQUINOLONES MOA: Similar to 8-aminoquinolines and Naphthoquinones a.Diiodohydroxyquin CLINICAL USE: b.Iodochlorhydroxyquin - Treatment for amoebiasis - Antifungal -Iodochlorhydroxyquin 4 –AMINOQUINOLONES MOA: Inhibition of hemoglobin degradation causing amino acid a.Chloroquine starvation of the parasite b.Quinacrine CLINICAL USE: c.Quinine - Quinine and Chloroquin- for malaria treatment - Chloroquin has anti-inflammatory property, used for rheumatoid arthritis and discoid Lupus erythematosus - Quinacrine-used for giardiasis in dogs INHIBITORS OF NUCLEIC ACID SYNTHESIS OF PROTOAS AROMATIC DIAMINES a.Pentamidine MOA: b.Phenamidine isothionate Binds with DNA and disrupts phosphoglyceride synthesis. c.Diaminazene Aceturate Diamines and Phentharidines at low doses specifically affects (Beneril,Ganaseg) kinetoplast DNA synthesis in trypanosomes CLINICAL USE: Diaminazene aceturate  Trypanosomiasis: active against T. congolense an T. vivax less on T. brucei and T. evansi for treatment  but no prophylactic effect  For bovine trichomoniasis and babesiosis Phenamidine - also used for Babesiosis ADVERSE EFFECTS Well tolerated by ruminants ,less in horses Adverse reactions seen in dogs-used as “sanative” drug CARBANILIDE DERIVATIVES a. Imidocarb dipropionate MOA: (imidocarb) -uncertain, but it has been suggested that it acts against T. brucei by interfering with polyamine production, and against B. ovis by blocking the entrance of inositol into erythrocytes (Bacchi et al., 1981; McHardy et al., 1986; Sasanelli et al., 2010). CLINICAL USE :  One of the tx of choice for babesiosis infections  Babesia canis and gibsoni, babesia caballi, theileria equi  Tx for hepatozoonosis (H. canis)  treatment of Cytauxzoon infection in cats  Feline babesiosis is refractory to treatment with imidocarb.  Control parasympathetic side effects with atropine b. Amicarbalide Amicarbalide (Diampron®) is effective against bovine babesiosis when given IM at 5–10 mg/kg BW PHENANTRIDINES OR AMINOPHENANTHRIDIUMS a. Homidium Bromide (Br) MOA: Inhibit DNA polymerase and DNA primed RNA b. Dimidium Br polymerase as a result of intercalation of the drugs with c. Pyrithidium Br DNA which leads to a local unwinding and lengthening of the d. Isometamidium DNA helix and thus interfere with its function as primer in the nucleic acid synthesis CLINICAL USE:  For the treatment of Trypanosomiasis (T.vivax and T. congolense)  Less active to T. brucei  Inactive against T. evansi DRUGS INTERFERING WITH PROTEIN SYNTHESIS OF PROTOZOAS AMINOQUINALDINS Quinapyrine Chloride or MOA: act by displacing Mg2+ and polyamines from the methylsulfate (Antrycide) cytoplasmic ribosomes of trypanosomes causing ribosomal aggregation and inactivation CLINICAL USE:  treatment for trypanosomiasis (T. congolense,T. vivax,T. equiperdum and T. equinum - chloride salt, water insoluble is for treatment -methylsulfate salt, water soluble is used for prophylaxis DRUGS WITH UNKNOWN MECHANISM OF ACTION (ANTI-COCCIDIA DRUGS) 1. Clopidol aka SPECTRUM: Coccidiosis, Leucocytozoon sp. Metrichlorpindol - Administered in feed from day old to slaughter at 0.0125% but should not be given to layers producing egg for human consumption - active against the sporozoite stage, allowing host cell penetration but not parasite development - has activity against second-generation schizogony, gametogony, and sporulation. - Sporozoites can resume development after the medication is removed 2. Nicarbazine SPECTRUM: Coccidiosis 4,4′-dinitrocarbanilide + 2-hydroxy- 4,6-dimethylpyrimidine MOA:precise mode of action is not known CLINICAL USE:  Chickens: fed for the prevention, but not the treatment, of coccidiosis. It is not labeled for laying hens. ADVERSE EFFECTS: -interrupts egg laying period, reduced hatchability, mottled egg yolk 3. Dinitolmide (Zoalene) CLINICAL USE: Anticoccidia for chickens and turkeys but not and Aklomide for layers  act primarily on the first-generation schizonts, and dinitolmide inhibits sporulation of oocysts  Dinitolmide is coccidiostatic if given for 6 days but is coccidiocidal if given for longer periods  4. Halofuginone SPECTRUM: Coccidiosis, theileriosis.  active against the asexual stages of coccidia  Anticoccidia for chickens and turkeys but not layers Skin (causes skin tears)and eye irritant  For Cryptosporidiosis and Theleiria infxns in cattle OTHER ANTI-COCCIDIA DRUGS A. TRIAZINE DERIVATIVES DICLAZURIL TOLTRAZURIL PONAZURIL SPECTRUM: Sarcocystis neurona, coccidiosis, toxoplasmosis, Neospora caninum, Neospora hughesii. MECHANISM OF ACTION  act on the apicoplast, present in apicomplexa parasites that may play a vital role in biosynthesis of amino acids and fatty acids, assimilation of nitrate and sulfate, and starch storage Triazine derivatives Clinical use 1. Diclazuril a. anticoccidia mix with feeds(broilers/turkeys not layers) b. Sarcocystis neurona (inhibit merozoite prod’n) c. Equine protozoal myeloencephalitis (EPM) in horses tx (5mg/kg) 2. Toltrazuril a. Anticoccidia –nursing pigs, calves, lambs; isospora (dogs and *(broadspectrum) cats) b. EPM in horses c. Hepatozoonosis in dogs 3. Ponazuril (active a. EPM and Sarcocystis neurona-horses metabolite of toltrazuril) b. Anticoccia- swine,dogs, cats (isospora) c. Neospora caninum in calves B. GUANIDINE DERIVATIVE ( ROBENIDINE)  SPECTRUM: Coccidiosis MECHANISM OF ACTION - Possibly inhibit the respiratory chain phosphorylation and ATPase activity in coccidia - Both coccidiostatic and coccidiocidal  active against the firstgeneration schizont of E. tenella by preventing formation of merozoites. CLINICAL USE: - For prevention and treatment of coccidiosis in poultry but not to layers C. THIAMINE ANALOGUES (AMPROLIUM) SPECTRUM: Coccidiosis MOA: competitive inhibition of active thiamine transport into the parasite. - acts on the first-generation schizont to prevent merozoite production - CLINICAL USE: -anticoccidia in chicken, turkeys, dogs, cats, cattle, goats, pheasants -Maybe used in layers as preventive medication against coccidia ADVERSE EFFECT  Polioencephalomalacia in treated animals (prolonged, high dose)  Bleeding disorder- necessary add Vit K in the diet to reduce mortality  No withdrawal required Learning Activities Individual activity: Write in your drug index the common antiprotozoal drugs used in veterinary medicine. Include their indications, contraindications and the different doses in animals and the available preparations in the market. Supplemental Web links or resources Reading assignments 1. Common Protozoans That Infect Domestic Animals https://veteriankey.com/common-protozoans-that-infect-domestic-animals/ 2. Treatment and Drug Therapies of Coccidiosis in carnivores:https://www.sciencedirect.com/science/article/pii/B9780128113493 000189 Flexible Teaching Learning Activity Modality (FTLM) Adapted Modular and Online ASSESSMENT TASK 1.1 In a table form make a list of antiprotozoal drugs used for the following conditions Coccidiosis Isospora Eimeria Cryptosporidiosis Sarcocystis Ehrlichiosis Toxoplasmosis Leishmaniasis Babesiosis HOW AM I DOING? I need more help to I do not completely I understand the Learning learn this understand the topic today REFERENCES 1.Riviere , JE and Papich, MG. 2018. Veterinary Pharmacology and Therapeutics.10 th ed.Wiley Blackwell.USA.pp 1,128-1,159. 2.Duszynski, D. Treatment and Drug Therapies of Coccidiosis in carnivores:https://www.sciencedirect.com/science/article/pii/B9780128113493000189