Pharmacology 3: Antiprotozoal & Anthelmintic Drugs PDF

Pharmacology 3 Antiprotozoal Drugs Anthelmintic Drugs Dr. Lina Tamimi  Introduction Parasites causing human disease can be broadly grouped into two main categories: 1. unicellular protozoa 2. multicellular helminths The protozoa have many subgroups: primarily...

Pharmacology 3 Antiprotozoal Drugs Anthelmintic Drugs Dr. Lina Tamimi  Introduction Parasites causing human disease can be broadly grouped into two main categories: 1. unicellular protozoa 2. multicellular helminths The protozoa have many subgroups: primarily intestinal primarily extraintestinal. The helminths are subdivided into: nematodes (roundworms) trematodes (flukes) cestodes (tapeworms).  MALARIA Four species of plasmodium typically cause human malaria: 1. Plasmodium falciparum 2. P vivax 3. P malariae 4. P ovale. The stage of gametocytes also develop in erythrocytes before being taken up by mosquitoes, where they develop into infective sporozoites.  tissue schizonticides: blood schizonticides gametocides  Life cycle An anopheline mosquito inoculates plasmodium sporozoites to initiate human infection. Circulating sporozoites rapidly invade liver cells exoerythrocytic stage: tissue schizonts mature in the liver. Merozoites are subsequently released from the liver and invade erythrocytes. Only erythrocytic parasites cause clinical illness.  In P falciparum and P malariae infection: only one cycle of liver cell invasion and multiplication occurs liver infection ceases spontaneously in less than 4 weeks. Thus, treatment that eliminates erythrocytic parasites will cure these infections.  In P vivax and P ovale infections: a dormant hepatic stage the hypnozoite is not eradicated by most drugs… failure in treatment Primaquine can kill hypnozoite Treatment needs 1. Eradication of both erythrocytic and hepatic parasites is required to cure these infections …… months to years 2. usually requires two or more drugs.  Drug classification 1. tissue schizonticides: Drugs that eliminate developing or dormant liver forms 2. blood schizonticides: those that act on erythrocytic parasites 3. gametocides: prevent transmission to mosquitoes (mosquito GUT) No single available agent can reliably effect a radical cure, ie, eliminate both hepatic and erythrocytic stages. Few available agents are causal prophylactic drugs, ie, capable of preventing erythrocytic infection before they increase sufficiently in number to cause clinical disease Drugs of choice: Antimalarials  1. QUINOLINE DERIVATIVES Agents 1. chloroquine 2. amodiaquine 3. quinine 4. quinidine 5. mefloquine 6. primaquine: the only medication for elimination of hypnozoites. 7. lumefantrine 8. halofantrine.  MOA against the erythrocytic stage of infection primaquine also kills intrahepatic forms and gametocytes. 1- drugs accumulate in the parasite food vacuole and forming a complex with heme that prevents crystallization in the Plasmodium food vacuole. 2- Heme polymerase activity is inhibited, resulting in accumulation of cytotoxic-free heme.  1.1. CHLOROQUINE Chloroquine has been the drug of choice for both: 1. Treatment and chemoprophylaxis of malaria since the 1940s, but its usefulness against P falciparum has been seriously compromised by drug resistance. 2. It remains the drug of choice in the treatment of sensitive P falciparum and other species of human malaria parasites.  It rapidly terminates fever (in 24–48 hours) clears parasitemia (in 48–72 hours) Chloroquine has been replaced by other drugs artemisinin-based combination therapies, as the standard therapy to treat falciparum malaria in most endemic countries. Chloroquine is the preferred chemoprophylactic agent in malarias regions without resistant falciparum malaria. Eradication of P vivax and P ovale requires a course of primaquine to clear hepatic stages. Contraindications & Cautions 1. Chloroquine is contraindicated in patients whom it may precipitate acute attacks of these diseases: Psoriasis Porphyria: porphyrin https://www.niddk.nih.gov/health-information/liver- disease/porphyria 2. generally not be used in those with retinal or visual field abnormalities or myopathy. Chloroquine should be used with caution in patients with a history of liver disease or neurologic or hematologic disorders.  interfere with the absorption The antidiarrheal agent kaolin of calcium- and magnesium-containing antacids chloroquine should not be co-administered with the drug. Chloroquine is considered safe in: 1. pregnancy 2. young children. 1.2. Quinine exists in oral and parenteral forms. 1.3. Mefaloquine is available as an oral formulation used as treatment or prophylaxis for all susceptible malaria species. Side effects can limit tolerability.  Adverse effects for all QUINOLINE DERIVATIVES QT prolongation/ quinidine. Hypoglycemia/ quinidine and quinine. Hemolysis in G6PD deficient patients/ primaquine. Insomnia, vivid dreams, and mood swings to depression, psychosis, and suicide/ mefloquine Cinchonism (tinnitus, headache, nausea, and visual disturbances) is common in patients receiving therapeutic doses of quinine.  2. Antibiotic Tetracycline: Tetrac. target prokaryotic Doxycycline: Tetrac. protein synthesis. Clindamycin: macrolide They are typically paired with fast-acting antimalarials (usually quinine).  3. ANTIFOLATES Sulfonamides Pyrimethamine Proguanil Dapsone These drugs act synergistically to target enzymes involved in folate synthesis……….. a pathway required for parasite DNA synthesis. Dapsone Proguanil  3.1. Sulfadoxine-pyrimethamine: Pyrimethamine: targets dihydrofolate reductase (DHFR) Sulfadoxine acts on dihydropteroate synthase (DHPS). Sulfadoxine-pyrimethamine is available in a fixed-dose tablet …… why??? not considered a combination therapy…..WHY??? because the components act on enzymes in the same pathway  3.2. Atovaquone-proguanil Interferes with two separate pathways involved in the biosynthesis of pyrimidines essential for nucleic acid replication. Atovaquone: blocks the parasite mitochondrial electron transport chain Proguanil: inhibits parasite dihydrofolate reductase through its active metabolite, cycloguanil. Proguanil also appears to act via a direct mechanism outside the folate pathway, enhancing atovaquone's mitochondrial membrane toxicity.  3.3. Artemisinins Act by binding iron…………. breaking down peroxide bridges in heme. leading to the generation of free radicals that damage parasite proteins………………. killing blood stages of all Plasmodium species as gametocytes They act rapidly reducing the parasite biomass. 3.3.1. Artesunate (Artemisinin Derivative) superior to quinine for treatment of severe malaria with respect to clearing parasitemia and reducing mortality. Artemisinin-based combination therapy :combines 1. highly effective short-acting artemisinins 2. longer-acting partner to: protect against artemisinin resistance facilitate dosing convenience. Lumefantrine is available only as a fixed dose combination with artemether which is now the first line therapy for uncomplicated falciparum malaria in many endemic countries Pyronaridine It is now available in combination with artesunate  Amebiasis Is infection with Entamoeba histolytica. 1. asymptomatic intestinal infection 2. mild to moderate colitis 3. severe intestinal infection (dysentery: diarrhea with blood) ameboma: annular colonic granulation 4. liver abscess 5. extraintestinal infections. The choice of drugs for amebiasis depends on the clinical presentation.  1- Asymptomatic Intestinal Infection carriers are not treated in endemic areas in nonendemic areas ……. treated with a luminal amebicide. A tissue amebicidal drug is unnecessary. Agents luminal amebicides: 1. diloxanide furoate 2. Iodoquinol 3. paromomycin.  Each drug eradicates carriage in about 80–90% of patients with a single course of treatment. Therapy with a luminal amebicide is also required in the treatment of all other forms of amebiasis.  2- Amebic Colitis 3- dysentery Treatment of choice Metronidazole plus luminal amebicide alternatives Tetracyclines and erythromycin alternative drugs for moderate colitis but not effective against extraintestinal disease. Dehydroemetine can also be used emetine but are best avoided because of toxicity.  4- Extraintestinal Infections Treatment of choice metronidazole plus a luminal amebicide. A 10-day course of metronidazole cures over 95% of uncomplicated liver abscesses. unusual cases in which therapy with metronidazole has failed: Aspiration of the abscess 1 addition of chloroquine 2 repeat course of metronidazole 3 Dehydroemetine and emetine are toxic alternative drugs. Drugs of choice: 1. Metronidazole chemical reduction of the nitro group of metronidazole by anaerobic bacteria Sensitive protozoans Reactive reduction products responsible for antimicrobial activity It inhibits nucleic acid synthesis by disrupting the DNA of microbial cells. 2. Tinidazole The mechanism is the same. Clinical Uses (both) A. Amebiasis Metronidazole or tinidazole all tissue infections with E histolytica. Alone….. Not effective against luminal parasites must be used with a luminal amebicide to ensure eradication of the infection. B. Giardiasis (INTESTINAL INFECTION) Metronidazole is the treatment of choice for giardiasis. The dosage for giardiasis is much lower—and the drug thus better tolerated— than that for amebiasis. Efficacy after a single treatment is about 90%. Tinidazole is at least equally effective.  C. Trichomoniasis Metronidazole is the treatment of choice. A single dose of 2 g is effective. Metronidazole-resistant organisms can lead to treatment failures. Tinidazole may be effective against some of these resistant organisms.  3. IODOQUINOL Iodoquinol ….. is a halogenated hydroxyquinoline. It is an effective luminal amebicide commonly used with metronidazole to treat amebic infections  MOA The mechanism of action of iodoquinol against trophozoites is unknown. It is effective against organisms in the bowel lumen but not against trophozoites in the : 1. intestinal wall 2. extra intestinal tissues Adverse effects Infrequent: diarrhea—which usually stops after several days anorexia, nausea, vomiting, abdominal pain, headache, rash, and pruritus. The drug may increase protein bound serum iodine Some halogenated hydroxy-quinolines can produce severe neurotoxicity with prolonged use at greater than recommended doses.  African trypanosomiasis 1. Pentamidine to treat the early hemolymphatic stage of disease caused by Trypanosoma brucei gambiense (West African sleeping sickness). tsetse flies Pentamidine should not be used to treat late trypanosomiasis with CNS involvement. 2. Suramin for the treatment of early East African sleeping sickness. Treatment choices MOA Pentamidine appears to bind to and disrupt the function of transfer RNA inhibition of protein synthesis.  Adverse effects Pentamidine is a highly toxic drug, with adverse effects noted in about 50% of patients receiving 4 mg/kg/d. Rapid IV administration can lead to: severe hypotension Tachycardia Dizziness Dyspnea so the drug should be: administered slowly (over 2 hours) patients should be recumbent and monitored closely during treatment. With IM administration: pain at the injection site is common sterile abscesses may develop. Pancreatic toxicity is common. Hypoglycemia due to inappropriate insulin release often appears 5–7 days after onset of treatment, can persist for days to several weeks may be followed by hyperglycemia. Reversible renal insufficiency is also common.  Other adverse effects include: rash metallic taste Fever gastrointestinal symptoms abnormal liver function tests acute pancreatitis Hypocalcemia Thrombocytopenia Hallucinations cardiac arrhythmias Inhaled pentamidine: is generally well tolerated but may cause: cough, dyspnea, and bronchospasm Anthelmintic Drugs: Benzimidazoles Agents Albendazole Mebendazole the most toxic Thiabendazole can cause CNS adverse effects These drugs are used primarily to treat infections caused by helminthes (worms): ranging from the common pinworms found in children to pathogens causing massive cystic lesions in the brain.  MOA The benzimidazoles interfere with elongation of the microtubules that are responsible for parasitic cellular structure leading to a disruption of growth and division. Most intestinal worm infections: a single dose of these drugs tissue-invasive disease: prolonged courses are necessary.  Case study A 5-year-old American girl presents with a 1-week history of intermittent chills, fever, and sweats. She had returned home 2 weeks earlier after leaving the USA for the first time to spend 3 weeks with her grandparents in Nigeria. She received all standard childhood immunizations, but no additional treatment before travel, since her parents have returned to their native Nigeria frequently without medical consequences. Examination reveals a lethargic child, with a temperature of 39.8°C (103.6°F) and splenomegaly. Initial laboratory studies are remarkable for hematocrit 29.8%, platelets 45,000/mm3, creatinine 2.5 mg/dL (220 μmol/L), and mildly elevated bilirubin and transaminases. A blood smear shows ring forms of Plasmodium falciparum at 1.5% parasitemia. What treatment should be started?  Case study answer This child has acute falciparum malaria, and her lethargy and abnormal laboratory tests are consistent with progression to severe disease. She should be hospitalized and treated urgently with intravenous artesunate or, if this is unavailable, intravenous quinine or quinidine. She should be followed closely for progression of severe malaria, in particular neurologic, renal, or pulmonary complications, and if treated with quinine or quinidine should have cardiac monitoring for potential toxicities.