Antiprotozoals Pharmacology 125 PDF

ANTIPROTOZOALS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 The antimetabolite that Martin Shkreli OUTLINE...

ANTIPROTOZOALS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 The antimetabolite that Martin Shkreli OUTLINE monopolized in the United States. Pyrimethamine (Enzyme that it targets is I. ANTIPROTOZOALS specific sa toxoplasma.) A. NITROIMIDAZOLES AND DILOXANIDE Others (Bloodborne): Leishmania, Trypanosoma i. METRONIDAZOLE, TINIDAZOLE ii. DILOXANIDE A. NITROIMIDAZOLES AND DILOXANIDE II. MALARIA A. PROPHYLAXIS i. METRONIDAZOLE, TINIDAZOLE B. QUINOLONES Bacterial Infections: i. CLASSIFICATIONS ○ Niche: Infections in the gut; anaerobic. ii. MECHANISM OF ACTION Giardia lamblia: Giardiasis ○ Intestinal; prominent ang diarrhea kasi nasa iii. INDICATIONS intestines. iv. ADVERSE DRUG REACTION Entamoeba histolytica: Amoebiasis v. INTERACTIONS ○ Intestinal vi. PHENANTHRENES: Trichomona vaginalis: Trichomoniasis HALOFANTRINE, LUMEFANTRINE ○ Vaginal; Sexuallty-Transmitted Infection C. ARTEMISININS AND OTHER ACT First-line ang Metronidazole. PARTNERS Mnemonic: GET out of her way. D. OTHERS i. ATOVAQUONE-PROGUANIL ii. DILOXANIDE MOA: Currently unknown; kills trophozoites. ○ Mechanism of action (MOA) is unknown; I. ANTIPROTOZOALS huwag na lang aralin. Unlike fungi, protozoa do not have cell walls but ○ Trophozoites: Growing on animals. they have multi-layered cytoplasms. “Troph” means autotroph. ○ They will overlap with bacteria, but they still “Zo” comes from zoology. have unique targets. Growing cells of protozoa. Single-Celled Eukaryotes ○ Prodrug is Diloxanide furoate. ○ Cytoplasmic Membrane, Organelles Indication: Intraluminal Amebiasis ○ Outer Cytoplasm: Ectoplasm (Asymptomatic) ○ Inner Cytoplasm: Endoplasm ○ Intraluminal: “Inside the space” of the Intestinal Protozoa intestines. ○ Giardia lamblia ○ Kapag ang amoeba ay static lang, as opposed ○ Entamoeba histolytica to invasive, hindi siya papasok sa cells, nasa ○ Cyclospora cayetanensis lumen pa lang siya; asymptomatic (go for ○ Immunocompromised: Cyclosporidium, Diloxanide). Isospora belli Adverse Drug Reactions: Human immunodeficiency virus (HIV): If ○ More on gas and vomiting ang side effects. CD4 cells are down, they are already ○ Flatulence immunocompromised. ○ Vomiting “Hindi lalabas unless wala na ang immune ○ Pruritus system.” ○ Urticaria Sexually transmitted: Trichomonas vaginalis ○ Anorexia Vector-Borne: Plasmodium, Babesia ○ Babesia is a parasite that causes babesiosis; it II. MALARIA infects erythrocytes and is transmitted by ticks Vector: Anopheles Mosquito (Cleveland Clinic, n.d.). ○ One of the two vector-born protozoans. Other Immunocompromised Protozoan Infections Vector-borne means may animal carrier. ○ Pneumocystis jiroveci ○ May animal na nagca-carry sa kanya; mosquito, Pneumonia; co-trimoxazole is given for six specifically yung Anopheles mosquito. months as maintenance; until Parasite mag-normalize ang CD4 count. ○ Plasmodium falciparum An example na ginagawang ○ P. malariae (Quartan Malaria) maintenance ang antibiotic. ○ P. knowlesi ○ Toxoplasma gondii ○ P. vivax (Tertian) PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Mahusay, Magalued, Mendoza Page 1 of 4 ANTIPROTOZOALS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 ○ P. ovale (Tertian) Acridine Derivative and Amodiaquine Side Chain: Life Cycle Pyronaridine ○ Mosquito Bite ○ Blood Sporozoites ii. MECHANISM OF ACTION ○ Liver ⟶ Schizonts Containing Merozoites Accumulate in food vacuole ⟶ prevent (Exoerythrocytic) biocrystallization of heme to hemozoin ⟶ ○ Schizont Rupture ⟶ Blood Merozoites (Invade accumulation of toxic heme in parasite. Other Cells) ⟶ Erythrocytes (Erythrocytic) ○ Heme, a breakdown product of hemoglobin, is ○ Maturation ⟶ Trophozoites ⟶ Schizonts a hemoglobin content of RBC. Malarial ○ Merozoites ⟶ Gametocytes ⟶ Mosquito parasites love hemoglobin but Heme is toxic to ○ Dormant: Hypnozoites (P. vivax, P. ovale) them. They need to digest Heme. They digest ○ Plasmodium yung protozoa; carrier yung it by crystallizing the heme in hemozoin. If you Anopheles. stop the hemozoin from crystallizing, heme ○ The mosquito will bite you and as it draws will increase making it toxic to the parasite. blood, the parasite Plasmodium will enter the ○ It is important to note that heme is toxic to blood and invade the liver. these parasites; also known as free heme As it invades the liver, it will become toxicity. schizonts in the liver and invade other Digestive vacuoles need to digest them, or cells, like erythrocytes. They will cause else heme will kill them. these cells to burst. Afterward, schizonts They store heme as hemozoin para hindi will invade other red blood cells. siya toxic. ○ Mosquitoes eat blood and may schizonts na ○ If we want to kill the parasites, we want to sila; they can carry it na. increase heme. ○ Liver ⟶ Blood ⟶ Gametes ⟶ Back to Mosquito ○ Chloroquine does interfere with hemozoin ○ Hypnozoites can slumber in the liver. crystallization. Incubation: Two to Four Weeks Heme increases dahil dito. Pre-exposure Prophylaxis (PrEP): Mefloquine ○ Why is there antimalarial resistance still, if it doesn’t really bind to the protozoal A. PROPHYLAXIS component? Mosquito Bite Prevention The digestive vacuole is involved; there is a ○ Kung may ipon na tubig, regularly check it transporter that allows passage of because if it is stagnant, breeding ground na molecules into the vacuole, the transporter siya for mosquitos. is the one that can mutate. ○ Avoid Outdoor Exposure (Dusk to Dawn) Mutates transporter, not the crystal. ○ Reduce Skin Exposure Blood Schizonticides: Quinine, Chloroquine, ○ Insect Repellant Mefloquine Chemoprophylaxis ○ Chloroquine stops heme crystallization. ○ For places with many malaria cases. ○ Chloroquine resistance is rising; it is no longer ○ Treatment: Quinolones recommended in monotherapy. In the Philippines, Doxycycline is given. Paired with artemisinin. Artemisinin is plant-based. B. QUINOLONES ○ Artemisia annua - Artemisinin derivites have Endoperoxide i. CLASSIFICATIONS bridge, when combined with iron, Quinolone Methanol it will break the bridge and release ○ Quinine free radicals. It kills the parasite ○ QuinidineI ○ Use Chloroquine alone if illness is severe and ○ Mefloquine other options are not available; resistance will Not FDA-registered. increase, however. 4-Aminoquinolines Gametocidal, Hypnozoites: Primaquine ○ Chloroquine For Primaquine, considered siya na radical ○ Amodiaquine drug kasi pati yung hypozoites and ○ Bisquinoline gametocites napapatay niya. ○ Piperaquine A radical cure prevents relapses in patients 8-Aminoquinolines (Galappaththy et al., 2013). ○ Primaquine ○ Tafenoquine iii. INDICATIONS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Mahusay, Magalued, Mendoza Page 2 of 4 ANTIPROTOZOALS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 Regardless of Chloroquine Sensitivity; Adjunct to Myopathy Artemisinin-Based Combination Therapy (ACT): Peripheral Neuropathy Pyronaridine, Artesunate Individual ○ First-Line ○ Mefloquine: Neuropsychiatric adverse drug ○ Monotherapy: Parenteral for severe malaria or reactions (e.g., depression, abnormal dreams, unavailability of Artemisinin-based psychosis). Combination Therapy (ACT). Nasa PNF pero hindi FDA-registered. Unavailable in the Philippines. DANGER: Possible Antimalarial BLACK BOX WARNING: Mefloquine blocks Resistance that is why it is not acetylcholinesterase. used as monotherapy Second mechanism of action (MOA) ○ Complicated Malaria, Alternative: IV Quinine ng Mefloquine. Not first-line. Acetylcholine will increase → bind to Quinine was the first-line drug in the past NOTE muscarinic at nicotinic receptors. “Mapait” daw. ○ We don’t have enough It can still be used for malaria pero information on this. Maybe a first-line pa rin ang ACT. combination of M and N Radical Cure (Elimination of Dormant Liver receptors. Hypnozoites): Primaquine ○ NOT for pregnant women; Chloroquine is Attributable to acetylcholinesterase given. inhibition (see note above). ○ Dormant liver hypnozoites; sleeping parasites ○ Quinine, Primaquine, Tafenoquine in the liver. Hemolytic anemia in G6PD patients (may ○ Also has efficacy for pre-erythrocytic and ganito rin sa sulfonamides). gametocyte stages. ○ Quinine Malaria Chemoprophylaxis Cinchonism: Tinnitus, headache, nausea, ○ Pregnant Women: Chloroquine first, then abdominal pain, and blurred vision. Primaquine after childbirth. Cinchonism is a syndrome; it is a Babesiosis, Alternative: Quinine, Clindamycin cluster of dose-related side effects ○ First-Line: Azithromycin, Atovaquone caused by Quinine. Side-effects are ○ We don’t have Atovaquone in the reversible (Kuhlmann & Fleckenstein, Philippines (it’s like saying Ethosuximide for 2017). absence seizures kahit wala talaga siya dito). Likely direct retinal toxicity. Hydroxychloroquine can be used for iv. ADVERSE DRUG REACTIONS malaria, but it is more used for lupus. General Similar to its cousin, ○ Nausea, vomiting, and abdominal pain. hydroxychloroquine is directly toxic to ○ CNS: Headache, appetite loss, malaise, and the retina. blurring of vision. This is just a hypothesis. ○ Urticaria, transient pruritus for 48 to 72 hours Hypoglycemia (especially in dark-skinned individuals, those IV: Thrombophlebitis unresponsive to anti-H1). ○ Amodiaquine: Agranulocytosis, Hepatotoxicity ○ QT Prolongation (Prolonged Use) ○ Rare Impaired Hearing v. INTERACTIONS Confusion Cation-Containing Antacids Psychosis ○ Reduce Quinine, Chloroquine absorption via Seizures adsorption. Agranulocytosis Exfoliative Dermatitis vi. PHENANTHRENES: HALOFANTRINE, Alopecia LUMEFANTRINE Bleaching of Hair Halofantrine Hypotension ○ DO NOT TAKE WITH FOOD.. ECG Change ○ Common Adverse Drug Reactions ○ Prolonged (Rheumatologic) Abdominal Pain Irreversible Ototoxicity Diarrhea Retinopathy Vomiting PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Mahusay, Magalued, Mendoza Page 3 of 4 ANTIPROTOZOALS PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Jarvin Enosh T. Tan, RPh, MA | HYNITH: BSP 2023 | YEAR 2 SEM 1 | AY 2024-2025 Cough Hemolysis Rash Elevated Liver Enzymes Headache Allergic Reactions Pruritus Delayed Hemolysis Elevated Liver Enzymes Interactions ○ Dose-related prolongation of QT and PR ○ Artemether: CYP3A4 Inducer intervals; rare instances of dangerous ○ Artemether-Lumefantrine: CYP3A4 arrhythmias and deaths. Substrates ○ Contraindication: Cardiac conduction defects or recently taken mefloquine; pregnancy. D. OTHERS Lumefantrine Kung wala sa Pilipinas, wala sa exam. ○ TAKE WITH FOOD. ○ Adverse drug reactions are more due to i. ATOVAQUONE-PROGUANIL malaria or other medications; QT prolongation Mechanism of Action (MOA) is clinically insignificant. ○ Atovaquone: Blocks the parasite’s mitochondrial electron transport chain (ETC). C. ARTEMISININS AND OTHER ACT PARTNERS ○ Proguanil: Metabolized to Cycloguanil, inhibits Artesunate, Arthemether, Dihydroartemisinin malarial dihydrofolate reductase. ○ Not likely to be seen routinely in Indications (Blood Schizonticide, Gametocidal) malaria-prevalent communities. ○ Chemoprophylaxis for falciparum malaria. Availability as Artemisinin-Based Combination Advantage: Shorter Duration Therapy (ACT) Disadvantage: OD Dosing, More Expensive ○ Pyronaridine, Artesunate ○ Treatment of falciparum malaria. ○ Artemether-Lumefantrine (AL)* (Not ○ Alternative for P. jiroveci (inferior to FDA-Registered): Take with food. co-trimoxazole). Accessed via the Department of Health Adverse Drug Reaction (DOH) Malaria Medicines Access Program. ○ Abdominal Pain ○ Artesunate-Amodiaquine (AS+AQ) ○ Nausea, Vomiting, Diarrhea ○ Artesunate-Mefloquine (ASMQ) ○ Headache ○ Dihydroartemisinin-Piperaquine (DHAP): Do ○ Insomnia NOT take with food. ○ Rash (More common with higher dose.) ○ Artesunate + Sulfadoxine-Pyrimethamine ○ Reversible elevations in liver enzymes. (AS+AP) Plasma concentrations of Atovaquone decreased MOA: Combined with Fe ⟶ endoperoxide bridge about 50% by Tetracycline, Rifampicin. cleavage ⟶ free radicals. ○ The free radicals kill the parasite. ○ Mechanism of action ng artemisinin derivatives. Kinetics ○ Absorption of Artemether-Lumefantrine is improved with food. ○ Half-life is very short. Arthemether: 1-2 Hours Artesunate: 0.3 Hours Indications: ○ First-line drug for falciparum malaria, regardless of Chloroquine sensitivity as ACT. ○ Complicated Malaria, First-Line: IV/IM Artesunate ○ Malaria chemoprophylaxis as ACT. Adverse Drug Reaction ○ Probably due to malaria (the disease itself). ○ Nausea, vomiting, diarrhea, headache, and dizziness. ○ Rare Neutropenia Anemia PHARM 125 (PHARMACOLOGY FOR PHARMACY 1) Carles, Chua, De Guzman, Go, Mahusay, Magalued, Mendoza Page 4 of 4