Antiprotozoals - 3 BS PHARMACY | PHARM 26 PDF

# **3 BS PHARMACY | PHARM 26** ## **ANTIPROTOZOALS** Protozoans are a diverse unicellular, eukaryotic, motile, heterotrophic organism. They are either parasites or free-living and their complex subcellular features allow them to survive the rigorous environments. ### **Life stages of these protoz...

# **3 BS PHARMACY | PHARM 26** ## **ANTIPROTOZOALS** Protozoans are a diverse unicellular, eukaryotic, motile, heterotrophic organism. They are either parasites or free-living and their complex subcellular features allow them to survive the rigorous environments. ### **Life stages of these protozoa:** 1. **Proliferative stages (e.g., trophozoites)** - protozoan in feeding stage of its life cycle 2. **Dormant cysts** - cyst enables parasitic species to survive outside of a host Though this organism is beneficial in wastewater treatment processes and soil fertility, its invasion of the human body threatens to develop different human diseases. The following are some common disease examples. | Protozoan | Disease | Transmission | | ------------------- | --------------- | ------------------------------------------------------------------------------ | | Entamoeba histolytica | Amoebiasis | Contaminated water or food | | Giardia lamblia | Diarrhoea | Contaminated water or food | | Plasmodium | Malaria | Mosquitoes | | Leishmania | Visceral disease | Sand flies | | Trichomonas vaginalis | Inflammation of urogenital tract | Sexually transmitted disease | | Trypanosoma brucei gambiense | African sleeping sickness | Tsetse fly | | Cryptosporidium | Watery diarrhoea | Waterborne outbreaks | | Toxoplasma gondii | Toxoplasmosis | Ingestion of undercooked meat | **LET'S GET FOCUS!** The most common diseases will be discussed in this report. 1. Amebiasis 2. Malaria 3. Leishmaniasis 4. Tropanosomiasis (T.brucei ) ## **PHARMACOLOGY 2** ### **1. AMOEBIASIS** Also known as "amebic dysentery". An infection of the intestinal tract caused by Entamoeba histolytica. About 90% of infections are asymptomatic. Remaining 10% produce a spectrum of clinical syndromes. #### **Epidemiology** - India -15% prevalence according to sanitation level and clinical diagnostic criteria #### **Symptoms** - **Diarrhea:** This can be frequent and may contain mucus or blood. - **Abdominal Pain:** Cramping and discomfort are common. - **Nausea and Vomiting:** Some people may experience these gastrointestinal symptoms. - **Loss of Appetite:** A decreased desire to eat can occur. - **Weight Loss:** This can result from prolonged diarrhea and loss of appetite. - **Fatigue:** General weakness and tiredness may develop. - **Fever:** A mild fever may be present in some cases. - **Dehydration:** Due to severe diarrhea, dehydration can occur, leading to additional complications. #### **Agent factors** AGENT- pathogenic strains of E. histolytica - E. histolytica exists in two forms: - vegetative (trophozoite) and - cystic forms. - **Trophozoites:** live in the colon where they multiply and encyst. - **The cysts:** are excreted in stool. Ingested cysts release trophozoites which colonize the large intestine. #### **Environmental Factor** - Low socio-economic status - Poor sanitation, sewage contamination - Night soil for agriculture - human feces for fertilizer - Seasonal variation (more in rainy season). #### **Host factors** - Amoebiasis may occur at any age. - No gender or racial differences. - Severe in children, old, or pregnant women - they have low immune system. - Amoebiasis is frequently a household infection. When an individual in a family is infected, others in the family may also be affected. #### **Modes of transmission** 1. **Faecal-oral route** - Contaminated water and food - Direct hand to mouth (cysts under fingernails) - Vegetables irrigated with sewage polluted water 2. **Vectors:** - such as flies, cockroaches and rodents are capable of carrying cysts and contaminating food and drink. 3. **Sexual transmission:** - Sexual contact via oral-rectal route #### **CLINICAL PRESENTATION** - Most common type of amoebic infection is asymptomatic cyst passage. - The symptomatic disease occurs in less than 10 percent of infected individuals. The symptomatic group has been further subdivided into intestinal and extra intestinal amoebiasis. - **Intestinal amoebiasis:** - abdominal cramps with mild diarrhea to colitis and dysentery - **Extra-intestinal amoebiasis:** - Amoebic liver abscess #### **PREVENTION** **Primary prevention** - **a. Sanitation:** safe disposal of human excreta, good sanitary practice like washing hands after defecation and before eating. - **b. Water supply:** - water filtration (sand filters), boiling. - **c. Food hygiene:** - prevent fecal contamination of food and drink, vegetables washed with water or aqueous acetic acid (5-10%). - **d. Health education:** food handlers and public. **Secondary prevention** - **a. Early diagnosis** - Fecalysis - **b. Treatment** - Metronidazole (DOC) #### **TREATMENT FOR AMOEBIASIS** **Metronidazole (Flagyl)** **Class:** Nitroimidazole It's effective against a wide range of bacteria and parasites, making it a valuable tool in treating various infections. #### **MOA:** - Metronidazole works by interfering with the DNA of bacteria and parasites. It damages their genetic material, preventing them from replicating and causing further infection. - **Pregnancy Category:** B #### **Common Uses of Metronidazole** 1. **Bacterial Infections:** - Skin infections, Dental infections, Stomach and intestinal infections (including those caused by H. pylori), Pelvic inflammatory disease. 2. **Parasitic Infections:** - Trichomoniasis, Giardiasis, Amebiasis. **Metronidazole** is available in several forms: - **Oral tablets and capsules:** For ingestion - **Topical creams and gels:** For skin infections - **Vaginal creams and gels:** For vaginal infections #### **S/E:** - Nausea - Vomiting - Diarrhea - Loss of appetite ### **2. MALARIA** Malaria is an acute infectious disease caused by our species of the protozoal genus Plasmodium. It is transmitted to humans through the bite of a female Anopheles mosquito. **(Responsible for the transmission of malaria parasite to humans; Only female Anopheles mosquitoes bite humans to obtain blood for egg development.)** #### **4 SPCS. OF THE GENUS PLASMODIUM** 1. **Plasmodium falciparum:** - most dangerous species causing an acute, rapidly fulminating disease (affect someone suddenly and can escalate quickly). 2. **Plasmodium vivax:** - milder form of the disease 3. **Plasmodium malariae:** - common to many tropical regions 4. **Plasmodium ovale:** - rarely encountered Resistance acquired by the mosquito to insecticides, and by the parasite to drugs, has led to new therapeutic challenges, particularly in the treatment of P. falciparum. #### **Life Cycle Stages:** 1. **Sporozoite Injection:** - An infected female Anopheles mosquito bites a human and through the secretion of saliva, the parasite enters the body in the form of sporozoites. 2. **Liver Stage:** - Sporozoites migrate to the liver and invade liver cells. - Inside the liver cells, they multiply asexually, forming merozoites. 3. **Merozoite Release and Red Blood Cell Invasion:** - Merozoites are released from the liver cells and invade red blood cells. 4. **Trophozoite Stage:** - Inside the red blood cell, the merozoite develops into a ring-shaped trophozoite. 5. **Schizont Stage and Merozoite Release:** - The trophozoite matures into a schizont. - The schizont divides to produce multiple merozoites. - The red blood cell ruptures, releasing merozoites that invade new red blood cells, continuing the cycle. 6. **Gametocyte Formation:** - Some merozoites develop into male and female gametocytes within the red blood cells. 7. **Mosquito Infection:** - When a mosquito bites an infected human, it ingests gametocytes (bridge between humans and mosquitoes in the spread of malaria). - The sexual cycle of the parasite occurs in the mosquito's gut, leading to the formation of sporozoites, which are then ready to infect another human. #### **Additional Notes:** - Understanding the life cycle is crucial for developing effective malaria prevention and treatment strategies. #### **TREATMENT FOR MALARIA** **Atovaqoune--Proguanil (Malarone)** DOC for prevention or treatment of malaria caused by a parasite called Plasmodium falciparum. Effective for chloroquine- resistant strains of P. falciparum. #### **MOA:** - **Atovaquone:** It blocks the parasite's ability to produce energy by inhibiting its mitochondrial electron transport. - **Proguanil:** Its active form, cycloguanil, inhibits an enzyme called dihydrofolate reductase, which is crucial for the parasite's DNA synthesis. This disrupts the parasite's ability to multiply and grow. - Together, they act synergistically to kill multiple stages of the plasmodium life cycle making it very effective in treating and preventing malaria. #### **DOSE:** - **Adults:** 1 gram of atovaquone and 400 mg of proguanil once daily as a single dose taken three days in a row. - **Children weighing:** - 5-8 kg: 125 mg/50 mg (2 pediatric tablets) PO daily for 3 days. - 9-10 kg: 187.5 mg/75 mg (3 pediatric tablets) PO daily for 3 days. - 11-20 kg: 250 mg/100 mg (1 adult tablet) PO daily for 3 days. #### **Administration:** PO, with food or milk to enhance absorption. Taken at the same time each day. #### **Adverse Effects:** - Nausea, Vomiting, Abdominal pain, Anorexia, Diarrhea, Coughing, Oral Ulcers, hepatotoxicity #### **Contraindicated:** - Hypersensitivity to Atovaqoune-Proguanil and its derivatives. - Patient with kidney problems - **Pregnancy Category:** C #### **Drug Interactions:** - Rifampin - Tetracycline - Warfarin - Metoclorpamide ### **3. LEISHMANIASIS** **Leishmaniasis** - is a zoonosis - a disease of animals transmitted to humans. - This disease of the skin and oral mucous membrane is caused by an intracellular parasitic protozoan. - **Neglected tropical disease (NTD)** - Is a diverse group of conditions caused by a variety of pathogens (including viruses, bacteria, parasites, fungi and toxins) and associated with devastating health, social and economic consequences. - NTDs are mainly prevalent among impoverished communities in tropical areas, although some have a much larger geographical distribution. - Endemic in parts of the tropics and subtropics, including Central and South America, Central and Southern Asia, Africa, Europe, and Middle East. #### **PATHOGEN AND VIRULENCE FACTORS** **Leishmania** is the cause of leishmaniasis. It is a flagellated protozoan commonly hosted by wild and domestic dogs and small rodents. Infected female sand flies of the genera Phlebotomus and Lutzomyia transmit Leishmania from animals to humans through their bites. - Sand flies are usually most active at twilight, evening, and nighttime hours (dusk to dawn). Less common ways Leishmania can infect you include: - Through sharing needles. - Through a blood transfusion. - From a pregnant person to the fetus. #### **THREE CLINICAL FORMS OF LEISHMANIASIS** 1. **Cutaneous leishmaniasis (CL):** The most common form, involves large painless skin ulcers that form around bite wounds made by the disease vector. Scars remain when the lesions heal. 2. **Mucosal (Mucocutaneous) leishmaniasis (ML):** When skin lesions enlarge to encompass the mucous membranes of the mouth, nose, or soft palate. Damage is severe and permanently disfiguring. Other symptoms may include: runny or stuffy nose, nosebleeds and difficulty breathing. 3. **Visceral leishmaniasis (VL):** aka kala-azar, is a serious form of the disease caused by protozoan parasites Leishmania donovani and Leishmania infantum. It affects your internal organs, like your spleen and liver. It's fatal if left untreated. Common signs and symptoms include: weight loss, weakness, fever that lasts for weeks or months, enlarged spleen, enlarged liver, decreased production of blood cells, bleeding, dark or discolored patches of skin and swollen lymph nodes. #### **DIAGNOSIS** - Microscopic identification of protozoa in samples from cutaneous lesions, the spleen, or bone marrow. - Assays using antibodies to detect antigen confirm the diagnosis and identify the strain. - Genetic analysis using PCR is needed for definitive speciation. #### **TREATMENT FOR LEISHMANIASIS** **Sodium stibogluconate** Chemically referred to as sodium antimony(V) gluconate, is an antiprotozoal medication primarily used to treat leishmaniasis, a disease caused by protozoan parasites of the genus Leishmania. #### **MOA:** Sodium stibogluconate is a pentavalent antimony compound. Its mechanism of action is unknown. However, it has been suggested that the reduction in ATP and GTP (guanosine triphosphate) synthesis contributes to decreased macromolecular synthesis. #### **Administration:** Administered parenterally via IV or IM routes, with careful monitoring required during treatment to manage any potential side effects effectively. #### **S/E:** - Nausea, Vomiting, Abdominal pain, Loss of appetite, Muscle pain, Headache. #### **Adverse Effects:** - Prolonged QT interval, Anemia, Thrombocytopenia Cough, Substernal pain, Arthralgia, Myalgia, Pancreatitis. #### **Contraindications:** - Hepatic and significant renal impairment. - Concomitant use of amphotericin B and other drugs that prolong QT interval. #### **Special Precautions:** - Patient with CV disease, history of ventricular arrhythmias, risk factor. #### **Drug Interactions:** - Increased risk of cardiac arrhythmia with amphotericin B; allow a 14-day resting period between sodium stibogluconate treatment and amphotericin B therapy initiation. - Concurrent use with drugs that prolong QT interval (e.g. cisapride, astemizole, terfenadine) may increase the risk of torsade de pointes which may lead to ventricular arrhythmia. ### **4. AFRICAN SLEEPING SICKNESS** - Also known as African trypanosomiasis - Endemic in sub-Saharan Africa - A protozoan disease of the nervous system - Victims become so tired that they no longer eat, finally succumbing to come and death. - Untreated African trypanosomiasis is invariably fatal. #### **PATHOGENESIS AND VIRULENCE FACTORS** **Trypanosoma brucei** - kitenoplastid protozoan that causes African sleeping sickness. - Randomly changes its glycoprotein antigens when it replicates. - By the time a host's immune system produced antibodies against a given set of glycoproteins, the parasite has produced a new set, leaving the host's immune system constantly one step behind the parasite. #### **PATHOGENESIS AND EPIDEMIOLOGY** Newly hatched bloodsucking tsetse flies (Glossina) spread T. brucei among wild and domesticated mammals and people. During the infection, some trypanosomes enter the brain, spinal cord, and cerebrospinal fluid; others continue to circulate in the blood, where feeding tsetse flies pick them up. It occurs in equatorial and sub-equatorial savanna and riverine areas of Africa, where tsetse flies live. #### **SIGNS AND SYMPTOMS** 1. First, the wound created by the vector's bite (tsetse fly) becomes a lesion containing necrotic (dead) tissue and rapidly dividing parasites. 2. Next, the presence of parasites in the blood generates fever, swelling of lymph nodes, and headaches. 3. Finally, invasion of the central nervous system results in meningoencephalitis characterized by headache, abnormal neurological function, and extreme drowsiness. Symptoms develop within months to years after infection, depending on the strain of protozoan involved. #### **Diagnosis, Treatment, and Prevention** **Diagnosis** - microscopic observation of trypanosomes in blood, lymph, spinal fluid, or a tissue biopsy. **Treatment** - must begin as soon as possible (Pentamidine, Suramin, Melasoprol, Eflornithine) **Prevention** - broad application of insecticides has reduced the occurrence of African Sleeping Sickness. - Use of netting over beds, window screening, and long, loose-fitting clothing. No vaccine currently exists for African Sleeping Sickness. #### **TREATMENT** **EFLORNITHINE (Ornidyl)** DOC for second stage (CNS involved) West African Trypanosomiasis (Gambian Sleeping Sickness). - Causative agent: Trypanosoma brucei gambiense. - Trypanostatic drug (IV formulation). #### **MOA:** Not effective in East African Trypanosomiasis. - Causative agent: Trypanosoma brucei rhodesiense. - Melarsoprol for advance cases of West African Trypanosomiasis. Inhibits the enzyme ornithine decarboxylase (ODC) which halts the production of polyamines, thereby leading to cessation of cell division. #### **DOSE:** - **Visceral leishmaniasis** - Infant: not recommended. - Children: not recommended. - Adult: 400mg/kg/day divided QID IV x 14 days, THEN 300 mg/kg/day PO x3-4 weeks. #### **Administration:** Administered parenterally via IV or IM routes, with careful monitoring required during treatment to manage any potential side effects effectively. #### **S/E:** - Otitis media - Diarrhea - Vomiting #### **Adverse Effects:** - Neutropenia - Anemia - Thrombobocytopenia - UTI #### **Contraindication:** - Hypersensitivity to eflornithine or any ingredient in the formulation - **Pregnancy Category:** C #### **Food Interactions:** - Alcohol, Tobacco.