Antiprotozoal Drugs Presentation PDF

ANTIPROTOZOAL DRUGS MATTHEW AIDOO (M.Phil, MGCoP, B.Pharm) Department of Pharmacology and Toxicology School of Pharmacy and Pharmaceutical Sciences University for Development Studies, Tamale  OUTLINE INTRODUCTION PLASMODIUM AMEOBIASIS GIARDIASIS TRICHOMONIASIS TAXOPLASMOSIS LEI...

ANTIPROTOZOAL DRUGS MATTHEW AIDOO (M.Phil, MGCoP, B.Pharm) Department of Pharmacology and Toxicology School of Pharmacy and Pharmaceutical Sciences University for Development Studies, Tamale  OUTLINE INTRODUCTION PLASMODIUM AMEOBIASIS GIARDIASIS TRICHOMONIASIS TAXOPLASMOSIS LEISHMANIASIS TRYPANOMIASIS  INTRODUCTION Humans host a wide variety of protozoal parasites These protozoal can be transmitted by insect vectors: 1. Directly from other mammalian reservoirs or 2. From one (human) person to another. Because protozoa multiply rapidly in their hosts and effective vaccines are unavailable, Chemotherapy has been the only practical way to both treat infected individuals and reduce transmission.  INTRODUCTION The human immune system plays a crucial role in protecting against the pathological consequences of protozoal infections Thus, opportunistic infections with protozoa are prominent in persons with impaired immunity: 1. Infants 2. Individuals with cancer 3. Transplant recipients, 4. Persons on immunosuppressive drugs or extensive antibiotics 5. Persons with HIV infection  PLASMODIUM Plasmodium (genus) is the protozoal that causes malaria PLASMODIUM CYCLE OF TIME CYCLE IN PARASITE HUMANS Plasmodium Only erythrocytic 48 hours; Tertian Falciparum cycle malaria Plasmodium Only erythrocytic 72 hours; Quatrain Malariae cycle malaria Plasmodium Only erythrocytic 24 hours knowlesi cycle Plasmodium vivax Both erythrocytic 48 hours; Tertian and malaria exoerythrocytic cycle  ASEXUAL CYCLE (HUMANS) 1. Sporozoites –from the mosquitos salivary glands are introduced into the host bloodstream, within 30min they disappear from the blood and enter into the parenchyma of the liver cells. 2. Tissue Schizonts –sporozoites develop and mature into hepatic schizonts. Formation of hepatic schizonts takes 5–15 days depending on the plasmodium species. The hepatic schizonts further develop (merozoites) and rapture to liberate merozoites into blood circulation.  ASEXUAL CYCLE (HUMANS) 3. Merozoites – bind and enter red blood cells, and develop into motile intracellular parasites called early trophozoites, which initiates the erythrocytic cycle. 4. Blood Schizonts – early trophozoites mature into late trophozoites which further mature into blood schizonts rapture to release another batch of merozoites, which causes the fever of malaria infection. 5. Hypnozoites – In P. vivax and P. ovale, after tissue schizonts rapture some dormant parasites, remain in the liver which can produce relapses of malaria infection. (Exoerythrocytic cycle)  ASEXUAL CYCLE (HUMANS) Once the hepatic (tissue) schizonts burst in P. falciparum, P. malariae, and P. knowlesi infections, no forms of the parasite remain in the liver (i.e. only erythrocytic cycle) The host’s haemoglobin is transported to the parasite’s food vacuole, where it is digested. Free haem, which would have been toxic to the plasmodium, is rendered harmless by polymerization to haemozoin in the parasite.  SEXUAL CYCLE (MOSQUITO) Takes in the female anopheles mosquito Some merozoites after entering RBCs differentiate into sexual forms of the parasite known as gametocytes After infected blood is ingested by a female anopheles mosquito, the female gametocyte is fertilized by male gametocyte in the mosquito gut to form a zygote The zygote, develops into an oocyte in the gut wall of the mosquito. The oocyte further develops, raptures and releases sporozoites, which invade the salivary gland of the mosquito When the mosquito bite a human, it delivers the sporozoites into blood circulation to begin an asexual cycle.  MALARIA IMMNUITY Sickle cell disease (SCD) The heterozygous state of the sickle cell gene (HbAS) confers protection against malaria probably through accelerated clearance of plasmodium falciparum-infected erythrocytes by macrophages. The homozygous state of the sickle cell gene (HbSS) is associated with increased morbidity and mortality. Splenic dysfunction may be responsible for increased susceptibility of HbSS patients to malaria as well as to other infections.  TARGETS OF DRUG ACTION CLASSIFICATION OF ANTIMALARIAL AGENTS The stage of the plasmodium cycle affected by the drug 1. Blood schizonticides 2. Tissue schizonticides Their intended use (either treatment or prevention) 1. Drugs for radical cure of malaria 2. Drug to treat acute malaria attack 3. Drugs for chemoprophylaxis of malaria 4. Drugs for prevention of malaria transmission  STAGE OF PLASMODIUM BLOOD SCHIZONTICIDAL AGENTS Act on the parasites in the blood (trophozoites) E.g. Artemisinins, quinine, mefloquine, chloroquine, pyrimethamine, proguanil, atovaquone Act on merozoites emerging from liver cells, blocking their entry into blood circulation and thus prevent the development of malarial attacks. E.g. Proguanil, Mefloquine, Pyrimethamine, Dapsone and Tetracyclines  STAGE OF PLASMODIUM TISSUE SCHIZONTICIDAL AGENTS Active against parasites in the liver (hypnozoites) E.g. Primaquine, Tafenoquine These drugs also destroy gametocytes and thus prevent transmission of infection by the mosquito. E.g. Proguanil, Primaquine, Tafenoquine, Pyrimethamine  INTENTED USE A. Drugs used to treat acute attack Blood schizonticidal agents E.g. Artemisinins, quinine, mefloquine, chloroquine, pyrimethamine, proguanil, atovaquone B. Drugs used for radical cure Tissue schizonticidal agents E.g. Primaquine, tafenoquine  INTENDED USE C. Drugs used for chemoprophylaxis Act on merozoites from liver cells blocking entry into RBCs and thus prevent the development of malarial attacks and not prevent malaria infection. E.g. Proguanil, Mefloquine, Pyrimethamine, Dapsone D. Drugs to prevent transmission Diminishes the human reservoir of the parasite and thus prevent malaria infection transmission. E.g. Proguanil, Primaquine, Pyrimethamine, Artemisinins. ARTEMISININ AND DERIVATIVES 1. Artemisinin is derived from the weed qing hao (Artemisia annua) 2. It is rapidly absorbed and widely distributed (lipophilic) 3. Artemisinin and derivatives are prodrugs converted in the liver to the active metabolite; dihydroartemisinin (DHA) 4. Artemisinins and derivatives generally have short half-lives 5. The endoperoxide bride in artemisinins is necessary for the antimalarial activity of artemisinins ARTEMISININ AND DERIVATIVES MECHANISM OF ACTION Artemisinins are believed to act via a two-step mechanism 1. Activation by intraparasitic heme-iron which catalyzes the cleavage of the endoperoxide bridge in artemisinins. 2. A resulting free radical intermediate kill the parasite by interfering with the conversion of free heme to hemozoin, also inhibits protein and nucleic acid synthesis of the plasmodium parasites during all erythrocytic stages. They are blood schizonticides and also act against gametocytes ARTEMISININ AND DERIVATIVES There are (3) semisynthetic derivatives of artemisinin Oral (dihydroartemisinin, artesunate, and artemether) Intramuscular (artesunate and artemether) Intravenous (artesunate) Rectal (artesunate) NB: When used alone, the artemisinins are associated with a high level of malaria parasite recrudescence (treatment failure) probably due to their short half lives. ARTEMISININ AND DERIVATIVES ARTESUNATE It is a water-soluble derivative of artemisinin; it is rapidly absorbed with peak plasma levels after 45 mins of IM inject. It has wide tissue distribution. Half-life is about 0.5–1.5 hrs (30 mins to 90 mins) It is given alone via IM, IV, (and rectally) for initial treatment of severe malaria for a minimum of 24 hours (0, 12 & 24 hr). This is followed by complete treatment course of appropriate PO artemisinin-based combination ARTEMISININ AND DERIVATIVES ARTESUNATE Adverse effects: Thrombocytopenia, Hyperbilirubinaemia, Anemia, Neutropenia, Hemoglobinuria, bradycardia, QT interval prolongation, elevated liver enzymes Caution: Patients with cardiovascular dxs, hepatic & renal impairment. Avoid concomitant use with drugs that prolong the QT interval. Contraindication: the first trimester of pregnancy unless benefit outweighs risk. Patients with hypersentivity. ARTEMISININ AND DERIVATIVES ARTEMETHER It is lipophilic methyl ether derivative of artemisinin; it is rapidly absorbed after IM injection. It has extensive tissue distribution. Half-life is about 2 hours It is given alone via IM only for initial treatment of severe malaria (stat loading dose, followed by daily for max 7 days) This is followed by complete treatment course of appropriate PO artemisinin-based combination antimalarial agent. It is available orally as combination: Artemether + lumefantrine ARTEMISININ AND DERIVATIVES ARTEMETHER Adverse effects: drowsiness, dizziness, hypotension, hypokalemia, Hypomagnesemia, prolongation of QT interval Caution: Avoid concomitant use with drugs that prolong the QT interval. Contraindication: the first trimester of pregnancy unless benefit outweighs risk. Patients with hypersentivity. Artemether is metabolized by CYP3A4 and should be avoided with inducers of CYP3A4 (e.g. rifampicin, carbamazepine, phenytoin) ARTEMISININ AND DERIVATIVES DIHYDROARTEMISININ A semi-synthetic derivative of artemisinin It is available only orally as combination drug for uncomplicated malaria (Dihydroartemisinin + Piperaquine) It is rapidly absorbed after oral administration. The elimination half life is about 4 hrs, eliminated by glucuronidation reaction. There is no sufficient data on its use in the first trimester of pregnancy, including all the artemisinin derivatives  ARTEMISININ BASED COMBINATIONS Thus oral forms artemisinins are used in combination with other antimalarial agents with longer half lives to ensure continual residual cure of the parasites. 1. Dihydroartemisinin (T1/2= 4hrs)+ Piperaquine (T1/2= 9.4 days) 2. Artemether (T1/2= 2 hrs)+ Lumefantrine (T1/2= 3–6 days) 3. Artesunate (T1/2= 0.5–1.5 hrs) + Amodiaquine (T1/2= 5 hrs), [desmethylamodiaquine, T1/2= 6–18 days] ARTEMISININ BASED COMBINATIONS LUMEFANTRINE It is metabolize to desbutyl-lumefantrine by CYP2D6. Inhibits the conversion of hemin [Fe3+] (oxidized heme[Fe2+]) to haemozoin (beta- hematin) and thus hemin cause oxidation of proteins, lipids and DNA in the parasite. Food enhances absorption of lumefantrine. SIDE EFFECTS – prolongation of QT interval, insomnia, myalgia, fatigue, palpitations. ARTEMISININ BASED COMBINATIONS LUMEFANTRINE Contraindications 1. Patients with history of prolongation of QT interval 2. Drugs that can prolong QT interval (Quinidine, amiodarone, sotalol, dofetilide), macrolides, fluoroquinolones, terfenadine. 3. Patients on drugs metabolized by CYP2D6 (e.g. metoprolol, imipramine, amitriptyline)  ARTEMISININ BASED COMBINATIONS AMODIAQUINE Active metabolite desethylamodiaquine by CYP2C8. The active metabolite accumulates in the digestive vacuole of the parasite and interfere with the detoxification of heme to hemazoin. SIDE EFFECT – agranulocytosis (extremely low granulocytes), hepatoxicity, neutropenia, pruritus, dystonia. Should not be used for prophylaxis, as its accumulation increases the risk of hepatotoxicity  ARTEMISININ BASED COMBINATIONS PIPERAQUINE Inhibition of haem detoxification pathway in the parasite is unknown but it is expected to be similar to that of chloroquine (accumulation in the digestive vacuole of the parasite and interfere with the conversion of heme to hemazoin) Side Effect – Dizziness, vertigo, nausea It is indicated for treatment of uncomplicated P. falciparum It is slowly absorbed and exhibits multiple  ARTEMISININ BASED COMBINATIONS PYRONARIDINE An erythrocytic schizonticide with potent antimalarial activity against multi-drug resistant plasmodium. It is chemically related to chloroquine It is indicated for treatment of acute malaria caused by P. falciparum and P. vivax Side Effect – headache, vomiting, nausea, abdominal pain, bradycardia, hypoglycemia QUINOLONES/RELATED COMPOUNDS QUININE A methanol quinolone derived from cinchona bark It is a blood schizonticidal drug against all P. parasites. It is NOT effective on gametocytes of P. parasites and exoerythrocytic parasites Quinine can also be given by slow IV infusion, IM & PO. Quinine should NOT BE GIVEN by bolus IV injection because of possible risk of hypoglycemia QUINOLONES/RELATED COMPOUNDS QUININE SIDE EFFECTS – bitter taste, nausea and vomiting, hypoglycemia, pruritus, flushing of the skin, fever, rash. Serious and life-threatening hematologic reactions; thrombocytopenia and hemolytic uremic syndrome/thrombocytopenia purpura Cinchonism – characterized by nausea, dizziness, tinnitus, headache and blurring of vision; occur if the plasma concentration of quinine exceeds 30–60 µmol/L. Excessive plasma levels may also cause hypotension, cardiac dysrhythmias, delirium and coma. QUINOLONES/RELATED COMPOUNDS QUININE Cautions 1. Acute hemolytic anemia 2. Atrial fibrillation or atrial flutter 3. Quinine stimulates release of insulin from pancreas, pregnant woman may experience clinically significant hypoglycemia QUINOLONES/RELATED COMPOUNDS QUININE Contraindications 1. Prolongation of QT interval 2. G6PD Deficiency (hemolysis) 3. Optic neuritis, myasthenia gravis 4. Thrombocytopenia purpura, hemolytic uremic syndrome 5. Hypersentivity reaction; cross sensitivity with mefloquine and quinidine QUINOLONES/RELATED COMPOUNDS MEFLOQUINE A methanol quinolone. It is a blood schizonticidal drug active against P. falciparum and P. vivax. It has NO EFFECT on hepatic forms of the parasites. Thus, treatment of P. vivax infections should be followed by a course of Primaquine to eradicate the hypnozoites. Mefloquine is given orally and is rapidly absorbed. It has a slow onset of action and a very long plasma half-life (up to 30 days) QUINOLONES/RELATED COMPOUNDS MEFLOQUINE SIDE EFFECTS – Transient CNS effects; giddiness, confusion, dysphoria and insomnia. Mefloquine is contraindicated in pregnant women or in those liable to become pregnant within 3 months of stopping the drug This is because of its long half-life and uncertainty about its teratogenic potential  QUINOLONES/RELATED COMPOUNDS CHLOROQUINE (oral and IM, only trophozoites) It has NOT EFFECT on sporozoites, hypnozoites or gametocytes. Its action derives from an inhibition of haem polymerase, the enzyme that polymerizes toxic free haem to haemozoin. P. falciparum is resistant to chloroquine in most parts of the world. This seems to result from enhanced efflux of the drug from parasitic vesicles due to of mutations in plasmodia transporter genes SIDE EFFECTS – Nausea and vomiting, dizziness and blurring of vision, headache and urticarial symptoms (itching). QUINOLONES/RELATED COMPOUNDS PRIMAQUINE (oral, hypnozoites) Etaquine and Tafenoquine are more active and slowly metabolized analogues of primaquine These drugs can effect a radical cure of P. vivax and P. ovale. Primaquine DOES NOT affect sporozoites and has little if any action against the erythrocytic stage of the parasite It has a gametocidal action, the most effective antimalarial for preventing transmission in all the species of plasmodia.  DRUGS AFFECTING FOLATE SULFONAMIDES AND SULFONES These inhibit synthesis of folate by competing with PABA The main sulfonamide used in malaria treatment is Sulfadoxine, and the only sulfone used is Dapsone. They are active against the erythrocytic forms of P. falciparum but are less active against those of P. vivax Have no activity against hypnozoites forms of the plasmodia  DRUGS AFFECTING FOLATE PYRIMETHAMINE Inhibit dihydrofolate reductase, which prevents the use of folate in DNA synthesis in the plasmodium. They act synergistically when used together with sulfonamides (Sulfadoxine/Pyrimethamine) It is taken once a week, plasma half-life of 4 days, and effective ‘suppressive’ plasma concentrations may last for 14 days Have no activity against hypnozoites forms of the plasmodia  DRUGS AFFECTING FOLATE PROGUANIL MOA same as pyrimethamine. It is also used in combination with sulfonamides to achieve synergistic effect. Additional effect on the hypnozoites of plasmodium but not on the hypnozoites of P. vivax. It is taken once daily, half-life is 16 hrs. It is a prodrug and is metabolized in the liver to its active form, cycloguanil, which is excreted mainly in the urine.  DRUGS AFFECTING FOLATE ATAVOQUONE It interferes with mitochondrial functions, such as ATP and pyrimidine biosynthesis, in susceptible malaria parasites. Atovaquone + Proguanil (Malarone) for prophylaxis and treatment of malaria. They act synergistically (proguanil enhances the membrane-collapsing activity of atovaquone) Side effects – abdominal pain, nausea and vomiting, diarrhea Pregnant or breastfeeding women should not take atovaquone  OTHER ANTIMALARIAL AGENTS TETRACYCLINES/CLINDAMYCIN Slow-acting blood schizonticides that are used alone for short-term prophylaxis in areas with chloroquine resistance. Their relative slowness of action makes them ineffective as single agents for malaria treatment. As an adjunct to quinine or quinidine, they are quite useful therapy for treatment of malaria. Tetracycline or Doxycycline are usually recommended. Clindamycin (Quinine + Clindamycin in pregnant women).  AMOEBIASIS Amoebiasis is caused by – Entamoeba dispar (90% infections) and Entamoeba histolytica (only 10% infections) However, only E. histolytica is capable of causing disease and thus requires treatment. Diseases: 1.Amoebic colitis 2. Amoebic liver abscesses Drugs of choice for amoebic infections (Nitroimidazoles) 1. Metronidazole 2. Tinidazole 3. Secnidazole  AMOEBIASIS Nitroimidazoles are well absorbed in the gut, but serum levels may not be therapeutic in the colonic lumen, and they are less effective against liver cysts. Luminal agents To eradicate E. histolytica trophozoites in the gut lumen. About 10% of patients will have relapse without luminal agents 1. Diloxanide furoate 2. Paromomycin 3. Iodoquinol 4. Nitazoxanide  GIARDIASIS Giardiasis is caused by the flagellated protozoan Giardia lamblia. Human-to-human transmission via the fecal- oral route. Infection with Giardia, can be asymptomatic carrier state, acute self-limited diarrhea, and chronic diarrhea. Nitroimidazoles (Metronidazole, Tinidazole, Secnidazole) are the drugs of choice for Giardiasis. Luminal agents (Paromomycin, Nitazoxanide) have been used with Nitroimidazoles for Giardiasis.  TRICHOMONIASIS Trichomoniasis is a sexually transmitted disease It is caused by the flagellated protozoan Trichomonas vaginalis. This organism inhabits the genitourinary tract of the human host, it causes vaginitis in women and, uncommonly, urethritis in men. Nitroimidazoles (Metronidazole, Tinidazole, Secnidazole) are the drugs of choice for Trichomoniasis.  TOXOPLASMOSIS It is caused by the protozoan Toxoplasma gondii. T gondii has (2) distinct life cycles The sexual cycle occurs only in cats (definitive host), and Asexual cycle occurs in mammals (humans). It consist of two (2) forms: 1. Tachyzoites (rapidly dividing form in acute phase infection) 2. Bradyzoites (slowly growing form in tissue cysts) Current drugs in the treatment of toxoplasmosis act primarily against tachyzoites form of T gondii, thus do not eradicate the cyst form (bradyzoites)  TOXOPLASMOSIS Pyrimethamine is the most effective agent for toxoplasmosis Sulfadiazine is usually added to pyrithemethamine The most effective available therapeutic combination is Pyrimethamine + Sulfadiazine or + Trisulfapyrimidines (e.g. sulfamerazine, sulfamethazine and sulfapyrazine). These agents are effective against tachyzoites and are synergistic when used in combination with pyrimethamine Alternative combination to pyrimethamine are: Clindamycin, Azithromycin, Clarithromycin, Atovaquone, Co-trimoxazole.  TOXOPLASMOSIS Folinic acid (Leucovorin) should be given concomitantly to prevent folate defiency of pyrimethamine. Spiramycin (macrolide), concentrates in placental tissue, is used for the treatment of acute acquired toxoplasmosis in pregnancy to prevent transmission to the fetus. Spiramycin does not cross the placenta and cannot be used to treat feotal toxoplasmosis. Dosing regimen, contraindication is necessary dependent of patients variables e.g. pregnancy, immune status.  CRYPTOSPORIDIOSIS It is caused by the protozoan Cryptosporidium parvum and Cryptosporidium hominis (only humans). It manifest as diarrhea Transmission is by infectious oocysts in feces either by direct human-to-human contact or by contaminated water Nitazoxanide (most effective agent), Paromomycin, and Azithromycin have activity against cryptosporidium Clofazimine is currently being studied in clinical trials in patients with AIDs for its effect on cryptosporidium.  LEISHMANIASIS It is caused by the intracellular protozoan Leishmania transmitted by the bite of a female phlebotomine sandfly. It manifest as self-limiting cutaneous ulcer to a mutilating mucocutaneous dxs or even to lethal systemic illness. Pentavalent antimony compounds [PAC] (Sodium stibogluconate, or Meglumine antimonate) are used for visceral and mucutaneous leishmaniasis Liposomal Amphotericin B – effective against  LEISHMANIASIS Miltefosine: an antitumor drug, which has been used to treat both visceral and cutaneous leishmaniasis. Pentamidine: effective against visceral leishmaniasis but associated with persistent diabetes mellitus and dxs recurrence. Oral ketoconazole, Itraconazole, Fluconazole, Allopurinol and Dapsone: are used but not effective as PACs. Topical Paromomycin: shown to be effective against cutaneous leishmaniasis  TRYPANOSOMIASIS The vector that causes trypanosomiasis is the tsetse fly In humans, trypanosomiasis is caused by three (3) main protozoan species. Trypanosoma gambiense and Trypanosoma rhodesiense, which cause sleeping sickness in Africa Trypanosoma cruzi, which causes Chagas’ disease in South America  TRYPANOSOMIASIS STAGES OF THE INFECTION Haemolymphatic stage – parasitaemia and fever as the parasite enters the blood circulation and lymphatic system Release of parasites and toxins to cause organ damage. 1. African sleeping sickness: when parasites reach the CNS causing somnolence and progressive neurological breakdown 2. Chagas’ disease: parasites damage the heart, muscles and sometimes liver, spleen, bone and intestines.  TRYPANOSOMIASIS African sleeping sickness Haemolymphatic stage: 1.Suramin (main agent) and 2.Pentamidine (alternative) Late stage of CNS trypanosomiasis: 1.Melarsoprol and 2. Eflornithine, these agents are toxic. Chagas’ disease (there is no totally effective treatment for this form of trypanosomiasis) 1. Eflornithine 2. Benznidazole and 3. Nifurtimox. THANK YOU