Antimalarial Drugs PDF

Antimalarial Drugs Wayne Parker, PharmD Drugs and Drug Classes to Consider Drugs for malaria CHLOROQUINE Mefloquine Quinine Primaquine Tafenoquine Doxycycline Atovaquone-proguanil (MALARONE) (Pyrimethamine-sulfadoxine (FANSIDAR)) Artemether-lumefantrine (COARTEM) Artesunate-mefloquine Objectives By...

Antimalarial Drugs Wayne Parker, PharmD Drugs and Drug Classes to Consider Drugs for malaria CHLOROQUINE Mefloquine Quinine Primaquine Tafenoquine Doxycycline Atovaquone-proguanil (MALARONE) (Pyrimethamine-sulfadoxine (FANSIDAR)) Artemether-lumefantrine (COARTEM) Artesunate-mefloquine Objectives By the end of this session, you should be able to: 1. Explain the molecular mechanism of action of the drugs. 2. Describe spectrum of action of each drug and how it relates to indications for prophylaxis and treatment. 3. Describe the pharmacokinetic properties of drugs in each class. 4. Describe the route of administration of drugs in each class. 5. Describe the main adverse effects and the main contraindications of the drugs in each class. 6. Describe the drug interactions of the drugs in each class. 3 Severe Malaria A 34-year-old Swiss man developed fever and diarrhea two weeks after returning from Madagascar. Before his visit he had not taken any prophylactic antimalarial drugs. Despite self-treatment with ciprofloxacin and metronidazole, he remained febrile. He also reported hematuria and dark urine. Examination of blood smears showed severe infestation with P. falciparum , with 70-80 % of red cells containing up to five parasites (small ring forms) per cell. The patient was treated with IV quinine sulfate and exchange transfusions, with dramatic improvement. Chalandon Y, Kocher A. N Engl J Med 2000;342:1715-1715. Some statistics as of 2021 In 2021 countries with zero indigenous cases for at least 3 consecutive years are considered to have eliminated malaria As of 2021: Ø ~ 247 million cases of malaria Ø ~ 619,000 deaths (mostly children) worldwide (CDC). Ø ~ 2,000 cases of malaria diagnosed in US each year (CDC). Ø Vast majority are travelers and immigrants returning from other countries (CDC). World malaria report 2022 https://www.who.int/malaria/en/ People in humanitarian need in malaria endemic countries as of December 2021 World malaria report 2022 Important Properties of Malaria Caused by plasmodium: vivax, ovale, malariae, and falciparum. Vivax and falciparum are more common P. Knowlesi emerging zoonotic malarial parasite (SE Asia) Vector/definitive host for plasmodia is the female Anopheles mosquito (female takes the blood meal). There are two phases in the life cycle: Sexual cycle, occurs primarily in mosquitoes. Asexual cycle, occurs in humans(intermediate host). From UptoDate FIRST LINE THERAPY is to PREVENT mosquito bites! Chemoprophylaxis and treatment Goal is to prevent mosquito bites (bed nets and insecticide) Chloroquine: areas with chloroquine-sensitive malaria Mefloquine or Atovaquone-proguanil or Artemetherlumefantrine: for most other areas Doxycycline: areas with a very high prevalence of multidrug resistant P. falciparum malaria Primaquine or tafenoquine: to eradicate liver forms (P vivax and ovale) Oral quinine/IV quinidine: to treat P falciparum malaria Add doxycycline (clindamycin for children) NEJM 359;6, 2008 Points of Intervention in the Progression of Infection with P. falciparum and potential vaccine. Cell Host & Microbe24, July 11, 2018 Vaccine targets RTS,S malaria vaccine in 2021 RTS,S/AS01 vaccine target Ø The WHO approved the RTS,S vaccine in October 2021. Ø According to WHO over 1 million African children received the first vaccine by April 25th, 2022. Wikipedia Rosenthal PJ. NEJM 2011;364:2549-2551. Majority of countries in Africa, including Ghana, account for 95 per cent of all malaria cases worldwide, and 96 % of deaths. Children under 5 account for 80 % of deaths in the region, according to the WHO. R21/Matrix-M 3 general categories: Artemisinins, chloroquine, mefloquine, quinine and quinidine, pyrimethamine, sulfadoxine, and tetracyclines: their action is directed against the asexual blood stages responsible for disease. The drugs treat, or prevent, clinically symptomatic malaria. Atovaquone and proguanil target the asexual erythrocytic forms and the primary liver stages of P. falciparum. Shortens to several days the required period for postexposure chemoprophylaxis. Primaquine is effective against primary and latent liver stages as well as gametocytes. Tafenoquine NEJM 359;6, 2008 Patient Presentation üGet a GOOD history including recent travel üSymptoms usually begin a few weeks after infection üHeadache üFever, cough, fatigue, malaise, shaking chills, arthralgia, myalgia üShivering and chills for 1-2 hours, then high fever, then excessive diaphoresis, and decreased body temperature üLess common – anorexia, lethargy, nausea, vomiting, diarrhea, jaundice üIf severe, patients may present with coma, seizures, anemia, renal failure, metabolic acidosis, respiratory distress, pulmonary edema, splenomegaly Algorithm for Management of Malaria 13 Algorithm for Management of Malaria Chloroquine For sensitive P falciparum and other species of malaria. Prophylaxis for travel to risk areas MOA: 1) inhibits DNA and RNA polymerase; interferes with metabolism and hemoglobin utilization by parasites; inhibits prostaglandin effects; 2) concentrates within parasite acid vesicles and raises internal pH resulting in inhibition of parasite growth; 3) may involve aggregates of ferriprotoporphyrin IX acting as chloroquine receptors causing membrane damage; may also interfere with nucleoprotein synthesis. ADME: Oral, absorbed from GI tract, sequesters in liver, spleen, lung, melanin-containing tissue. Excreted in the urine Long half-life, traces found in urine years after. Clinical uses of chloroquine: Acute attacks of malaria Blood schizonticide and gametocide P. vivax, P. ovale, P. malariae, P. knowlesi, and chloroquine-sensitive strains of P. falciparum. Does not eliminate dormant liver forms of P vivax and P ovale (primaquine added!!) For hepatic amebic abscesses that fail initial therapy with metronidazole Golan et al: Principles of Pharmacology 4th e. Chloroquine Adverse effects: Pruritus, in darker skin individuals Oral therapy (low dose): nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision, and urticaria Large IV doses: à severe hypotension, EKG changes (QRS widening, T wave abnormalities), myocardial depression and cardiac arrest. Prolonged treatment: hemolysis in G6PD-deficient persons, impaired hearing, confusion, psychosis, seizures, agranulocytosis, exfoliative dermatitis, alopecia, bleaching of hair Contraindications and cautions: Psoriasis or porphyria Retinal or visual field abnormalities or myopathy History of liver disease or neurologic or hematologic disorders Safe in pregnancy and young children ChloroquineToxic chloroquine Induced Hair retinopathy (Bull's-Eye Hypopigmentation Maculopathy) Donovan JC, Price VH. NEJM 2010;363:372-372. Nogueira HM, Gama RD. NEJM 2009;360:2224-2224 Quinine Derived from the bark of the cinchona tree Traditional remedy for intermittent fevers in South America MOA: Depresses oxygen uptake and carbohydrate metabolism; intercalates into DNA, disrupting the parasite's replication and transcription. Quinidine: more potent enantiomer of quinine, antiarrhythmic drug ADME: Oral, primarily metabolized in the liver and excreted in the urine. Half-life of quinine is higher in severe malaria Clinical uses: Treatment of chloroquine resistant P. falciparum malaria Effective blood schizonticide (against all four) Gametocidal against P vivax and P ovale Quinine is first-line therapy, in combination with clindamycin, for the treatment of infection with Babesia microti or other human babesial infections Quinine Adverse Effects: Cinchonism: tinnitus, headache, nausea, dizziness, flushing, visual disturbances. Hypersensitivity reactions: skin rashes, urticaria, angioedema, and bronchiospasm. Blackwater fever: intravascular hemolysis, hemoglobinemia, and hemoglobinuria leading to anuria renal failure and death (rare hypersensitivity reaction to quinine) Hematologic abnormalities: hemolysis (G6PD deficiency), leukopenia, agranulocytosis, and thrombocytopenia Hypoglycemia: through stimulation of insulin release Severe hypotension with rapid IV infusions of quinine or quinidine. EKG abnormalities: QT prolongation (IV quinidine) Contraindications and cautions: cinchonism, hemolysis, or hypersensitivity, underlying cardiac abnormalities Can raise plasma levels of warfarin and digoxin Renal insufficiency George JN et al. NEJM 2017;376:74-80. Quinine immune-mediated systemic reactions. Tombe M. NEJM 2008;358:1837-1837. Quinine + clindamycin or atovaquone + oral azithromycin for babesial infections Transmission of Babesia microti by the Ixodes scapularis Tick Fever and hemolytic anemia Predominantly in NE U.S.A Appears as “Maltese cross” Vannier E, Krause PJ. N Engl J Med 2012;366:2397-2407. Yager PH et al. N Engl J Med 2014;370:753-762. Mefloquine A synthetic 4-quinoline methanol related to quinine MOA: unknown, structurally similar to quinine, the destruction of the asexual blood forms of P. falciparum, P. vivax ADME: Given orally, highly protein-bound, extensively distributed in tissues, and metabolites of the drug are slowly excreted, mainly in the feces Long half life, a single-dose treatment regimen orally Clinical uses: For chloroquine resistant P falciparum Blood schizonticide (P falciparum and P vivax) Prophylactic use (with artemisinin) in regions with chloroquine-resistant strains Mefloquine Adverse effects: Nausea, vomiting, dizziness, sleep and behavioral disturbances, epigastric pain, diarrhea, abdominal pain, headache, rash, and dizziness. Black box warning: vivid dreams (common), significant neuropsychiatric signs and symptoms can occur Seizures and psychosis (rare) Contraindications and cautions: History of epilepsy, psychiatric disorders, arrhythmia, cardiac conduction defects, or sensitivity to related drugs Caution if quinine or quinidine is used (long elimination half life) Not safe in pregnancy Primaquine Synthetic 8-aminoquinoline, DOC for the eradication of dormant liver forms of P vivax and P ovale (tissue schinzonticide) MOA: metabolites of primaquine act as oxidation reduction mediators resulting in: 1.the generation of reactive oxygen species 2.interference of mitochondrial electron transport and binds to DNA in parasite. ADME: oral, dist. to tissues. Rapidly metabolized and excreted in the urine (induces CYP1A2) Clinical uses: to eradicate liver stages (Vivax and Ovale) and prevent a subsequent relapse chloroquine (blood schinzonticide) for acute attacks gametocidal against all 4 malaria species chemoprophylaxis: P. falciparum and Vivax p. jiroveci infection: combo with clindamycin, also alternative for pneumocystosis Primaquine Adverse effects: Nausea, epigastric pain, abdominal cramps, and headache Hemolysis or methemoglobinemia (manifested by cyanosis), in persons with G6PD deficiency or hereditary metabolic defects Leukopenia, agranulocytosis, leukocytosis (rare) Contraindications and cautions: History of granulocytopenia or methemoglobinemia Patients should be tested for G6PD deficiency Avoided in pregnancy: fetus is relatively G6PD-deficient and thus at risk of hemolysis Tafenoquine Tafenoquine is an 8-aminoquinoline antimalarial drug Active against liver forms including hypnozoite and erythrocytic forms, as well as gametocytes, of Plasmodium species, including P. falciparum and P. vivax. Activity against the pre-erythrocytic liver stage prevents development of the erythrocytic forms of the parasite, which are responsible for relapses in P. vivax malaria. Approved by FDA in 2019. Labeled Indications: Malaria, treatment (prevention of relapse) of P. vivax or P. ovale. Atovaquone Antimalarial highly active against P. falciparum MOA: Acts selectively on the mitochondrial cytochrome bc1 complex to inhibit electron transport and collapse the mitochondrial membrane potential (analog of coenzyme Q)!! For mild to moderate P. jiroveci pneumonia, and T. gondii infection Oral, eliminated unchanged in feces Adverse effects: fever, rash, nausea, vomiting, diarrhea, headache, and insomnia Malarone: combo atovaquone-proguanil (synergistic effect) Golan et al: Principles of Pharmacology 4th e Inhibitors of folate synthesis Sulfadoxine inhibits dihydropteroate synthase Pyrimethamine and proguanil inhibit plasmodial dihydrofolate reductase, key enzyme in the pathway for synthesis of folic acid. Proguanil: prodrug Antimalarial action Not used alone, effective in combination with other agents Sulfadoxine-pyrimethamine (FANSIDAR) Atovaquone-proguanil (MALARONE) Integrated Pharmacology 3rd edition Inhibitors of folate synthesis Clinical uses: Chemoprophylaxis: used in combination therapy Treatment of chloroquine-resistant falciparum malaria Fansidar (sulfadoxine-pyrimethamine) for uncomplicated falciparum malaria Sulfadiazine-pyrimethamine 1st line therapy for toxoplasmosis. Trimethoprin-sulfamethoxazole 1st line therapy for pneumocystosis caused by fungus P Jiroveci. Adverse effects and cautions: Well tolerated Mouth ulcers, allopecia (proguanil) Severe cutaneous reactions (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrosis) (fansidar) Fansidar use in pregnancy (controversial) Trimethoprin-sulfamethoxazole for P. jirovecii pneumonia infection or Primaquine + clindamycin Proposed Pneumocystis Life Cycle Posteroanterior Chest Radiograph of a 68-Year-Old Patient with Pneumocystis Pneumonia That Developed as a Consequence of Long-Term Corticosteroid Therapy for an Inflammatory Neuropathy Thomas CF Jr, Limper AH. N Engl J Med 2004;350:2487-2498. Sulfadiazine-pyrimethamine 1st line therapy for toxoplasmosis Chorioretinal Toxoplasmosis Hafidi Z, Daoudi R. NEJM 2014;370:361-361 Congenital toxoplasmosis abscesses in the putamen and thalamus Rubin’s Pathology Text 5th Edition Artemisinins: Artermether and Artesunate Active component of an herbal medicine used as an antipyretic in China for over 2000 years Prodrug, contain an endoperoxide that is activated by heme iron binding, resulting in oxidative stress, inhibition of protein and nucleic acid synthesis, ultrastructural changes, and a decrease in parasite growth and survival. Artemisinin and analogs Not used alone, combined with other antimalarials (mefloquine, lumefantrine) for 1st-line treatment Artesunate, a semisynthetic derivative of artemisinin. artesunate IV approved by FDA in 2020. Blood schizonticide against all malaria parasites. Not recommended for treatment in children younger that 5 or during first trimester of pregnancy Golan et al: Principles of Pharmacology 4th e. Lumefantrine The exact mechanism of lumefantrine is unknown. Shares structural similarities with mefloquine and halofantrine and is formulated with artemether. This combination is highly effective for the treatment of uncomplicated malaria and is the most widely used first-line antimalarial across Africa. Artemether-lumefantrine (Coartem) – preferred agent. Both artemether and lumefantrine inhibit nucleic acid and protein synthesis. Antibiotics Bacterial protein synthesis inhibitors appear to act against malaria parasites by inhibiting protein synthesis in the plasmodial prokaryote-like organelle, the apicoplast. Not active against liver stages None should be used as a single agent Tetracycline and doxycyline are active against erythrocytic schizonts of all human malaria parasites. Clindamycin is slowly active against erythrocytic schizonts and can be used when doxycycline is contraindicated (children and pregnant patient) Azithromycin and fluoroquinolones are being studied 32 Doxycycline Used in treatment of falciparum malaria in conjunction with quinine Used to complete treatment courses after initial treatment of severe malaria with IV quinine, quinidine, or artesunate 1 week treatment course Standard chemo-prophylactic drug in SE Asia in areas of high mefloquine resistance (i.e., Thailand) Adverse effects include GI, candida vaginitis, and photosensitivity 33 Copyrights apply References and Resources 1. UptoDate 2. Bertram G. Katzung: Basic and Clinical Pharmacology, 14th Ed. Chapter 52. 3. Laurence L. Brunton, Randa Hilal-Dandan, Bjorjn.C Knollmann: Goodman and Gilman’s: The Pharmacological Basis of Therpaeutics, 13e. Chapters 53 and 54 4. David E. Golan, Ehrin J. Armstrong, April W. Asmstrong: Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy Fourth Edition, 4e. Chapter 37 5. New England Journal of Medicine End Key Websites Centers for Disease Control and Prevention. Travelers’ Health. http://www.cdc.gov/travel/. World Health Organization. International travel and health. http://www.who.int/ith/. Algorithm for the Management of Malaria https://www.cdc.gov/malaria/resources/pdf/algorithm.pdf 37 Plasmodium vivax Microgametes A 31-year-old woman, 33 weeks pregnant, presented with a fever (40°C) and chills 2 months after returning from a trip to Brazil. A mixed infection of P. malariae and P. falciparum was diagnosed and treated with quinine….had a relapse one month after the diagnosis, and labor was induced because of fetal distress. A review led to a revised diagnosis of P. vivax, confirmed by PCR. …both mother and infant were treated with chloroquine. Subsequently, the mother was treated with primaquine for terminal prophylaxis, which the infant did not require since he was not exposed to the sporozoite... One year later, both mother and child are doing well, with no further relapses. Karplus R, Johnston SP. N Engl J Med 2006;354:1064-1064. Placental Malaria A 40-year-old Nigerian woman with a history of malaria was admitted at 36 weeks of pregnancy after 4 days of intermittent fever, with temperature of 104°F, and lower abdominal pain. The base-line fetal heart rate was 108 bpm, with late decelerations. An emergency cesarean section was performed, and a healthyappearing baby boy was born. Maternal malaria due to a mixed infection with P falciparum and P. malariae was diagnosed on the basis of a peripheral-blood smear. The mother was treated successfully with quinine sulfate and doxycycline. The infant was not ill. Miller IJ, Telford SR III. N Engl J Med 1996;335:98-98.