Antiprotozoal Drugs - PM 716 C52 PDF

PM 716 Antiprotozoal Drugs Chapter 52 Antiprotozoal Drugs Richard M. Rocco, PhD PM 719 C12 Antimalarial 1  Case Study A 9-year old boy with intense chills, high fever for 4 days, drenched in sweat, exhausted. Diarrhea, nausea, abdominal pain. The boy and...

PM 716 Antiprotozoal Drugs Chapter 52 Antiprotozoal Drugs Richard M. Rocco, PhD PM 719 C12 Antimalarial 1  Case Study A 9-year old boy with intense chills, high fever for 4 days, drenched in sweat, exhausted. Diarrhea, nausea, abdominal pain. The boy and his family had immigrated to the US from West Africa 3 weeks before his current illness. PM 719 C12 Antimalarial 2 Case Study Work-up included usual tests to rule out bacterial and viral infections. Thin-film blood smear for blood-born parasites confirms malaria. PM 719 C12 Antimalarial 3  Case Study Treat acute malaria with iv artesunate or iv quinine or quinidine. If quinine or quinidine is used cardiac monitor for potential toxicities. PM 719 C12 Antimalarial 4 Plasmodium falciparum One of 4 infectious protozoal parasites. Only P. falicparum causes life threatening illness. Four major stages in parasite development: ring, trophozoite, schizont, gametocyte. PM 719 C12 Antimalarial 5  Malaria Anopheles mosquito inoculates sporozoites into human host. Sporozoites infect liver cells (asexual stage) but mature into merozoites. Merozoites released from liver and invade RBCs where they feed on Hb maturing into trophozoites. Trophozoites divide in RBC into 16-32 new parasites. RBC ruptures and releases new parasites. Anemia results, pain from sickle cell trapping in capillaries, oxygen starvation from anemia etc. PM 719 C12 Antimalarial 6 Malaria 300 - 500 million cases worldwide per year. 41% of the world’s population lives in areas with endemic malaria. Malaria kills 3 million humans/year. P. vivax and P. falciparum account for 95% of the cases with P. faciparum the more serious infection. PM 719 C12 Antimalarial 7 Sickle Cell Trait Normal Hb contains two alpha and two beta globulin chains. In sickle cell Hb a single amino acid substitution occurs in the one beta chain (trait) or both beta chains (disease). (point mutation) Glutamic acid replaced with valine. PM 719 C12 Antimalarial 8  Malaria Sickle cell red cells are infected with the parasite similar to normal red cells, however decreased oxygen tension in sickle red cells causes sickle shape. Sickle shaped cells are removed from circulation in ~ 4 days compared to normal life span of red cell ~ 40 days. Parasite dies before maturity. PM 719 C12 Antimalarial 9  Malaria Treatment: the three “r” problems (1) Recrudescence: residual parasites remain, not destroyed by drug, lie dormant in RBC and reemerge. (2) Relapse: sporozoites lie dormant in liver. (3) Resistance: antimalarial drugs no long work. PM 719 C12 Antimalarial 10 Quinine Quinine the drug derived from the bark of the Cincohna tree. Discovered by Native South Americans in Andes of Peru. Taken back to Europe by 16th century Western explorers. The “Cardinal’s Cure” PM 719 C12 Antimalarial 11  Quinine Quinine isolated from the cincohna bark in 1820. ADRs called “cinchonism” which includes tinnitus, headache, nausea, dizziness, flushing, visual disturbances. May also cause hemolytic anemia in G6PD deficiency. MOA, parasite feeds on human hemoglobin, produces toxic heme which parasite sequesters into protective “cells” Quinine appears to block the ability of parasite to sequester toxic heme. PM 719 C12 Antimalarial 12  Quinine & Quinidine Both derived from the bark of the cinchona tree (originally grown in the Andes mountains). Quinidine is the dextrorotatory stereoisomer of quinine. Schizonticide against all four species of human malarial parasites. Exact mechanism unknown. PM 719 C12 Antimalarial 13  Quinine & Quinidine ADRs include cinchonism: tinnitus, headache, nausea, dizziness, flushing, visual disturbance. Hemolysis (red cells) can occur. Reduce dosage in renal insufficiency. PM 719 C12 Antimalarial 14 Quinacrine (Atabrine®) Yellow pills issued to all military personnel headed to the South Pacific in WWII. (not used today but teaches something) Required to be taken 3x per day po. Causes major GI disturbances and turns skin yellow. Non-compliance a major issue due to ADRs. PM 719 C12 Antimalarial 15 Quinacrine At the battle of Guadalcanal in Papua New Guinea (Aug 1942-Feb 1943) up to 75% of the hospitalizations were due to malaria and not war wounds. PM 719 C12 Antimalarial 16 B. B. Brodie (1909-1989) Goldwater Memorial Hospital on Roosevelt Island, NYC. Brodie is considered one of the founders of modern pharmacology. Determines that quinacrine is effective at reduced dosing. Lower doses prevent yellow skin and GI disturbances. PM 719 C12 Antimalarial 17  Chloroquine Not effective against liver stage parasites. MOA, same as quinine, blocks ability of the parasite to pack toxic heme into storage cells called “hemzoins.” Resistance: parasite develops a cell wall pump that blocks entry of drug into the cell PM 719 C12 Antimalarial 18  Chloroquine Drug of choice since 1940’s when resistance is not an issue. Synthetic drug, large Vd ~1000 L/Kg Drug causes buildup of free heme in red cell which is toxic to the parasite Side effects vary widely and can include cardiac changes (QRS widening, T-wave changes). PM 719 C12 Antimalarial 19  Amodiaquine Similar to chloroquine Used in combination drugs amodiaquine + artesunate amodiaquine + sulfadoxine + pyrmethamine PM 719 C12 Antimalarial 20 Artemisinin (ATN) Qinghaosu (pronounced Ching-how-sue) also called Artemisia annu plant, also sweet wormwood. Used in China for over 2000 years for fever reduction. Plant related to family that produces absinthe, tarragon, sagebrush. PM 719 C12 Antimalarial 21  ATN “Zhou Hou Bei Ji Feng” (Handbook of Prescriptions for Emergency Treatments) written by Ge Hong in 340 AD, herb used to treat fevers and chills. Li Shizen in 1546 in his Compendium of Materia Medica (Ben Cao Gang Mu) advocated its use to treat malaria. PM 719 C12 Antimalarial 22  ATN 50% of the world’s population at risk of contracting malaria. 250 million have malaria. 1 million die each year (primarily children in Africa). Mortality rate for serious infection is 20-50%. All current drugs have shown resistance. PM 719 C12 Antimalarial 23  ATN 1972 Artemisinin (ATN) extracted and isolated from Qinghaosu plant by Chinese researchers. 1979 X-ray crystallography used to determine structure. One of the few naturally occurring endoperoxid compounds. Semisynthetics produced to improve solubility. Artemether is one example in clinical trials. PM 719 C12 Antimalarial 24  ATN LD50 in mice 4228 mg/kg indicating possible low toxicity for humans. In vitro studies demonstrated effective against malarial parasite. In 1979 first reports of 2099 cases of malaria treated with ATN and success was almost 100% (Chinese Med J. 92:811 (1979). In a malaria epidemic in Vietnam in 1979, ATN reduced the death rate by 97%. PM 719 C12 Antimalarial 25  ATN ATN has been found to produce >90% rate of reversal of malarial symptoms. Parasite numbers in treated individuals go down within 8 hours and are cleared within 2 days. All chloroquine resistant strains have been destroyed by ATN. All Plasmodia forms pathogenic to humans have been destroyed by ATN. All stages of the parasite life-cycle destroyed by ATN. With 5 - 7 day dosage regimens, cure rates are > 90%. PM 719 C12 Antimalarial 26  ATN Drug derivatives (semisynthetics) are synthesized from ATN extracted from the plant. Total synthesis of ATN has been described but process too difficult and labor intensive. Cultivated plants produce 2% dry weight yield of ATN (wild plants yield ~ 0.3%). Plant takes 8 months to grow. Chloroquine (synthetic introduced in the 1940’s cost 20 cents/dose, ATN 90 cents/dose. The WHO has ordered 100 million doses ATN The Global Fund for AIDS, TB and Malaria will spend $450 million on this drug over next five years. PM 719 C12 Antimalarial 27  ATN Chloroquine-resistant strains of Plasmodium falciparum have developed worldwide. ATN is the only drug able to treat large numbers of the population living in parasite resistant locations. ATN has become the world’s most effective new drug for malaria in the last 100 years and the only new drug to treat malaria obtained from a natural herbal product since the discovery of quinine in 1530. PM 719 C12 Antimalarial 28  ATN Drug taken up into parasite infected RBC’s 100x more compared to non-infected cells. ATN kills parasite in nanomolar concentrations but requires micromolar concentrations to cause harm to mammalian cells. ATN may intercalate with proteins in the parasite, it may also set up free radical damage within the RBC that results in parasite death. PM 719 C12 Antimalarial 29  ATN Riamet® a combination of ATN derivative (artemether) and lumefantrine (a second antimalarial) widely sold in Europe for travelers. Combination therapy is required to prevent ATN resistance from developing. It took almost 400 years to discover a new highly effective antimalarial since quinine. Every drug since quinine has become resistant. PM 719 C12 Antimalarial 30 Plant Shortage PM 719 C12 Antimalarial 31 Drug Resistance PM 719 C12 Antimalarial 32  Mefloquine Often used to treat chloroquine-resistant strains of P. falciparum. Chemically related to quinine. Mechanism of action is unknown. Effective when used for prophylaxis. FDA black box warning about potential for neurological and psychiatric toxicities. PM 719 C12 Antimalarial 33  Primaquine Drug of choice for eradication of dormant liver forms of P. vivax and P. ovale and hepatic stages of all forms (unique to this drug) Can be used for chemo prophylaxis. Poor acticity against red cell stages ADRs are the usual. PM 719 C12 Antimalarial 34  Melarone Combination drug for treating malaria. Atovaquone (250 mg) + proguanil (100 mg) PO daily dosing can be used for prophylaxis. PM 719 C12 Antimalarial 35 Folate Inhibitors to Treat Malaria Mostly used in combination regimens. Pyrimethamine………related to trimethoprin (see Sulfa Chapter 46). Proguanil……biguanide derivative. Fansidar = sulfadoxine + pyrimethamine All are selective inhibitors of plasmodial dihydrofolate reductase, a key enzyme in folate synthesis. PM 719 C12 Antimalarial 36  Antibiotics To Treat Malaria Lumefantrine, only available in fixed combination with artemether (Coartem, Riamet) See notes in slides and book on artemisinin derivatives. PM 719 C12 Antimalarial 37  Amebiasis Treatment Infection with Entamoeba histolytica the cause of intestinal infections, colitis, dysentery, liver abscess. Metronidazole and tinidazole are drugs of choice to treat amebiasis, giardiasis and trichomoniasis. PM 719 C12 Antimalarial 38  Metronidazole & Tinidazole Nitro groups of the drugs are reduced by the protozoans, forming toxic compounds to the organism. ADRs include metallic tasting dry mouth, Metronidazole has a disulfiram-like effect, avoid alcohol ingestion. PM 719 C12 Antimalarial 39