Anti-parasitic agents_F23a.pdf

Pharmacology of Antiparasitic agents (& of Drugs for Opportunistic Infections) Aditi Marwaha, B.Pharm, Ph.D Instructional Associate Professor [email protected] PollEv.com/marwaha Learning Objectives 1. Know the stages of the malaria parasite in the human body. 2. Recognize the prototypes of antiparasi...

Pharmacology of Antiparasitic agents (& of Drugs for Opportunistic Infections) Aditi Marwaha, B.Pharm, Ph.D Instructional Associate Professor [email protected] PollEv.com/marwaha Learning Objectives 1. Know the stages of the malaria parasite in the human body. 2. Recognize the prototypes of antiparasitic agents. 3. Recognize the mechanisms of action, key pharmacokinetic features, and toxicities of antiparasitic agents. 4. Classify antimalarial drugs into those that are effective against only the blood stages of the parasite, those that are effective against both the blood and liver stages, and those that are effective against only the liver stages of the parasite. Parasites • Greek parasitos; para : along side of; sitos : food • Parasite  someone who eats at another’s table or lives at another’s expense. • Bacteria and viruses ? • Parasites  larger organisms, more complex than bacteria Classification of Parasites Parasites Protozoa 1. Unicellular 2. Eukaryotes 3. Internal parasites Helminths Ectoparasites 1. Multicellular 2. Worms 3. Internal parasites 1. Multicellular include arthropods 2. E.g. : Lice, mites, ticks 3. External parasites Protozoa Infections • Intestinal protozoa  GI illness • Entamoeba histolytica • Cryptosporidium • Giardia • Blood and tissue protozoa • • • • Plasmodium (malaria) Trypanosomes (Chagas disease) Toxoplasma (toxoplasmosis, opportunistic infection) Leishmania Malaria • • • • • • • Occurs in tropics, subtropics Africa is most affected continent Very rare in the US, Europe Transmitted by mosquito bite (female Anopheles) Caused by protozoa  Plasmodium sp. Protozoa infects red blood cells and liver Several species with distinct features: • • • • P. falciparum (common, with highest mortality) P. vivax (common) P. ovale (less common) P. malariae (low & isolated prevalence) Malaria – Life Cycle Exoerythrocytic stage: • Sporozoites invade hepatocytes • Mature into multinucleated schizonts • Liver schizonts rupture  6 to 30 days  merozoites • Asymptomatic Erythrocytic stage: Asexual stage  • Merozoites enter RBCs • Form trophozoites • Mature into multinucleated schizonts • RBCs schizonts rupture  merozoites • Merozoites  infect new red cells • Symptomatic Sexual stage  few merozoites differentiate into gametocytes Malaria – Life Cycle (Exoerythrocytic Stage) • Both P. vivax and P. ovale form dormant liver stages (hypnozoites) that can activate weeks, months, or years after the initial infection, causing relapse. RBC Pathophysiology – Malaria Parasite Exoerythrocytic stage: • Vegetative state • Hypnozoites (P. vivax and P. ovale)  late onset, relapse Erythrocytic stage: • Degrades intracellular proteins • RBC’s  irregular, less flexible, more antigenic • Extensive hemolysis  anemia, splenomegaly, cyclic fever Hb Heme Hematin Heme polymerase Hemozoin Food vacuole Comparing the Malaria Species Plasmodium falciparum Plasmodium vivax Plasmodium ovale Plasmodium malariae RBC preference RBCs of all ages Young RBCs (reticulocytes) Young RBCs (reticulocytes) RBCs of all ages Disease Severity End organ damage and death can occur End organ damage and Severe disease death less common uncommon than P. falciparum but can occur Severe disease rate Chloroquine resistance Yes Yes No Rare Relapses from liver (Hynozoites) No Yes Yes No Cycle in RBCs 48 hours 48 hours 48 hours 72 hours The Case of Don Francisco http://tmedweb.tulane.edu/pharmwiki/doku.php/treatment_of_malaria Don Francisco is a 24‐yr old landscaper who recently migrated to New Orleans from Northern Brazil. Approximately 4 months after his arrival he begins to experience episodes of flu‐like symptoms including fever, chills, fatigue and sweating. He goes to local free health clinic, where he is diagnosed with malaria, and given a prescription for chloroquine. His symptoms disappear soon after beginning chloroquine therapy, but several months later his symptoms reappear. Question 1: What is the most likely explanation for the return of Don Francisco’s fever? Question 2: What drug should be included in his treatment so that his illness will not return? Classification of Antimalarial Agents Antimalarial Agents Asexual erythrocytic stage Chloroquine Hydroxychloroquine Mefloquine Artemisinins Tetracycline/Doxycycline Asexual erythrocytic stage + Primary liver stages Atovaquone Proguanil Malarone (Atovaquone + Proguanil) Primary and latent liver stages Primaquine Tafenoquine The Case of Don Francisco http://tmedweb.tulane.edu/pharmwiki/doku.php/treatment_of_malaria Don Francisco is a 24‐yr old landscaper who recently migrated to New Orleans from Northern Brazil. Approximately 4 months after his arrival he begins to experience episodes of flu‐like symptoms including fever, chills, fatigue and sweating. He goes to local free health clinic, where he is diagnosed with malaria, and given a prescription for chloroquine. His symptoms disappear soon after beginning chloroquine therapy, but several months later his symptoms reappear. Question 1: What is the most likely explanation for the return of Don Francisco’s fever? Question 2: What drug should be included in his treatment so that his illness will not return? Susceptibility to Drugs of Malarial Parasites at Various Developmental Stages LIVER STAGES GROUP 1 DRUGS PRIMARY SPOROZOITE BLOOD STAGES HYPNOZOITE ASEXUAL GAMETOCYTE Artemisinins ‐ ‐ ‐ + + Chloroquine ‐ ‐ ‐ + +/‐ Mefloquine ‐ ‐ ‐ + ‐ Quinine/quinidine ‐ ‐ ‐ + +/‐ Pyrimethamine ‐ ‐ ‐ + ‐ Sulfadoxine ‐ ‐ ‐ + ‐ Tetracycline ‐ ‐ ‐ + ‐ 2 Atovaquone/proguanil ‐ + ‐ + +/‐ 3 Primaquine ‐ + + ‐ + Tafenoquine ‐ + + ‐ + ‐, no activity; +/‐ low to moderate activity; + clinically important activity Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e Classification of Antimalarial Agents Antimalarial Agents Chemoprophylaxis Chloroquine Mefloquine Malarone Doxycycline Primaquine Tafenoquine Treatment Artemisinin and Its Derivatives ACT Partner Drugs Lumefantrine Piperaquine Pyronaridine Atovaquone Sulfadoxine‐pyrimethamine Proguanil Chloroquine and Hydroxychloroquine Quinine and Quinidine Mefloquine Tafenoquine Sulfonamides and Sulfones Tetracyclines and Clindamycin RBC Mechanism of Action – Chloroquine • Drug of choice for both treatment and chemoprophylaxis • Chloroquine  weak base, concentrated in highly acidic food vacuoles • Binds to heme and disrupts its sequestration • Heme accumulation  toxic to the parasite • Usefulness against P falciparum ?  resistance • Effectiveness against: 1. 2. 3. Blood stage  Liver stage  Gametocytes  Parasite Hb Heme Hematin Heme polymerase Hemozoin Food vacuole Mechanism of Action – Chloroquine Resistance • Altered transporter residing in the membrane of food vacuole • Mutation in pfcrt (P falciparum chloroquine‐resistance transporter) gene • ↓ intravacuolar accumulation of chloroquine Chloroquine Pharmacokinetics Source: Packard RM. N Engl J Med 2014;371:397‐399 • Well absorbed orally, rapid IM, SC absorption • 60 % binding to plasma protein Therapeutic use: • Chemoprophylaxis of nonfalciparum and sensitive falciparum malaria • Used in auto‐immune disorders Adverse effects • Narrow therapeutic index • Low doses  GI irritation, skin rash and headaches • High doses  skin lesions, peripheral neuropathy, myocardial damage, retinal damage, auditory impairment and toxic psychosis Mefloquine Mechanism of Action • Block heme catabolism (similar to chloroquine) • Effectiveness against: 1. Blood stage  2. Liver stage  3. Gametocytes  Mechanism of Action of Resistance • Mutations in the PFMDR1 (P. falciparum multidrug‐resistance protein) gene Mefloquine Pharmacokinetics • Oral administration only (parenteral causes severe local reactions) • Long t1/2  13‐24 days (high lipophilicity, extensive binding, extensive tissue distribution) • Can be given once a week for chemoprophylaxis Therapeutic use: • Drug of choice for chemoprophylaxis against chloroquine‐resistant strains of malaria Mefloquine Adverse effects: • Nausea, vomiting • Dizziness, vestibular problems, tinnitus • Neuropsychiatric side effects (rare sometimes severe): • Anxiety/depression/psychosis • Seizures Contraindications: • History of epilepsy, psychiatric disorders, arrhythmia or drug sensitivity. Malarone (Atovaquone + Proguanil) • A fixed combination of atovaquone (250 mg) and proguanil (100 mg) Mechanism of Action • synergistic inhibitory effect on parasitic nucleic acid replication • Atovaquone  lipophilic analogue of ubiquinone • Binds to parasite mitochondria  disrupts mitochondrial electron transport • Broad‐spectrum activity against Plasmodium, P carinii, Toxoplasma gondii • Proguanil  prodrug (active metabolite cycloguanil) inhibits parasitic isoform of dihydrofolate reductase and also acts as an electron uncoupling agent • Effectiveness against: 1. Blood  2. Liver  3. Gametocytes  Malarone (Atovaquone + Proguanil) Mechanism of Action of Resistance • Mutations within a catalytic domain of the cytochrome bc1complex present within the parasite mitochondrial inner membrane. • Addition of proguanil markedly reduces the frequency of appearance of atovaquone resistance. Malarone (Atovaquone + Proguanil) ADME • Atovaquone absorption is slow and variable after an oral dose; absorption improves when the drug is taken with a fatty meal. Therapeutic Uses • Prophylaxis of Plasmodium falciparum malaria, including areas where chloroquine resistance has been reported. Adverse effects • Abdominal pain, vomiting, diarrhea, headache and pruritus Classification of Antimalarial Agents Antimalarial Agents Chemoprophylaxis Chloroquine Mefloquine Malarone Doxycycline Primaquine Tafenoquine Treatment Artemisinin and Its Derivatives ACT Partner Drugs Lumefantrine Piperaquine Pyronaridine Atovaquone Sulfadoxine‐pyrimethamine Proguanil Chloroquine and Hydroxychloroquine Quinine and Quinidine Mefloquine Tafenoquine Sulfonamides and Sulfones Tetracyclines and Clindamycin Doxycycline Mechanism of action Inhibits protein translation in the parasite apicoplast (organelle) Delayed death of the parasite • Effectiveness against: 1. Blood stage  2. Liver stage  3. Gametocytes  Adverse effects: Nausea, vomiting, diarrhea, abdominal pain, dizziness, vaginal candidiasis, photosensitivity Contraindications : Pregnant women Primaquine and Tafenoquine • Both are 8‐amino quinolones Mechanism of action • Is unclear • 14 metabolites detected, one or more reactive metabolites of primaquine  oxidative damage of parasite mitochondria  oxidative damage to human RBCs • Effectiveness against: 1. 2. 3. Blood stage  Liver stage  Gametocytes  Pharmacokinetics • Well absorbed from GI tract. Tafenoquine is a long half‐life analogue of primaquine. Source: Camarda, G., Jirawatcharadech, P., Priestley, R.S. et al. Antimalarial activity of primaquine operates via a two‐step biochemical relay. Nat Commun 10, 3226 (2019). Primaquine and Tafenoquine Therapeutic uses • Primary prophylaxis • Terminal chemoprophylaxis and radical cure of P. vivax and P. ovale (relapsing) infections • OIs (Primaquine) Adverse effects • GI disturbances, methemoglobinemia (self‐limited), fatal hemolysis in persons with G6PD deficiency Protozoa Infections • Intestinal protozoa  GI illness • Entamoeba histolytica • Cryptosporidium • Giardia • Blood and tissue protozoa • • • • Plasmodium (malaria) Trypanosomes (Chagas disease) Toxoplasma (toxoplasmosis, opportunistic infection) Leishmania Pyrimethamine Mechanism of action • Dihydrofolate reductase inhibitor • Inhibits folic acid synthesis for parasite nucleic acid acids • Highly selective against plasmodia and toxoplasma Pharmacokinetics • Slowly but completely absorbed from the gut Therapeutic uses • No longer recommended for treatment or chemoprophylaxis of malaria • Opportunistic infections : such as toxoplasmosis Adverse effects: skin rashes, reduced hematopoiesis. Leucovorin minimizes bone marrow suppression seen with pyrimethamine. Classification of Parasites Parasites Protozoa 1. Unicellular 2. Eukaryotes 3. Internal parasites Helminths 1. Multicellular 2. Worms 3. Internal parasites Ectoparasites 1. Multicellular include arthropods 2. Lice, mites 3. External parasites Helminths • Roundworms (nematodes) • Tissue • Intestinal  Enterobius vermicularis (pinworm) • Flatworms • Tapeworms • Flukes • All have three stages • Eggs • Larvae • Adults Pharmacological treatment • Many unique drugs used for therapy Benzimidazoles • Albendazole • Mebendazole Others: • Ivermectin • Pyrantel pamoate Benzimidazoles : Albendazole and Mebendazole Mechanism of action • Inhibit microtubule formation of pinworm Pharmacokinetics • Albendazole  erratic oral absorption, is a prodrug • Mebendazole  poor bioavailability Therapeutic uses • GI nematode infections Adverse effects • Well tolerated Ivermectin Mechanism of action • Induces tonic paralysis by activating a family of ligand gated Cl channels • Channel found only in invertebrates Therapeutic uses • Head lice (topical) • GI nematode infections (systemic) Pyrantel Pamoate Mechanism of action • Depolarizing NMBs • Induce persistent activation of nAch receptors in worms Pharmacokinetics • Poorly absorbed from GI tract Therapeutic uses • Alternative to mebendazole or albendazole for treating nematode infections Adverse effects • Transient and mild GI symptoms Other Drugs for OIs: Dapsone and Pentamidine • Dapsone  broad‐spectrum agent with antibacterial, antiprotozoal, and antifungal effects • Pentamidine  antiprotozoal and antifungal agent Therapeutic uses (Pentamidine) • treatment and prophylaxis of pneumonia caused by Pneumocystis jiroveci (PJP) Adverse effects (Pentamidine) • Highly toxic, IV  hypotension, tachycardia, hypoglycemia, nephrotoxicity • Inhaled pentamidine better tolerated Classification of Parasites Parasites Protozoa 1. Unicellular 2. Eukaryotes 3. Internal parasites Helminths 1. Multicellular 2. Worms 3. Internal parasites Ectoparasites 1. Multicellular include arthropods 2. Lice, mites 3. External parasites