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Lecture 2 Pharmacology of Anti-Parasitic Drugs Kumar PHARMACOLOGY of ANTI-MALARIA DRUGS

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Lecture 2 Pharmacology of Anti-Parasitic Drugs Kumar PHARMACOLOGY of ANTI-MALARIA DRUGS Lecture 2 Pharmacology of Anti-Parasitic Drugs Kumar PHARMACOLOGY OF ANTI-MALARIA DRUGS: PLASMODIUM SPECIES THAT CAUSE HUMAN MALARIA: CHLOROQUINE (& AMODIAQUINE): Plasmodium One cycle COMMENTS Drug of choice for both treatment and prophylaxis falciparum o Infection ceases spontaneously < 4 wk Rapidly and almost completely absorbed oral administration Responsible for most serious complications Acidic in nature/DNA and deaths SPECTRUM Blood schizonticide – all 4 strains Most likely to become drug resistant Gametocide – P. vivax, P. ovale and P. malariae Plasmodium One cycle MOA Exact pharmacological mechanism still debated but malariae o Infection ceases spontaneously < 4 wk o Changes in metabolic pathway & inhibits reproduction Plasmodium Dormant hepatic stage (hypnozoite) vivax Relapses occur 1. Parasite digests host cell’s hemoglobin to obtain essential AAs Not very common in African population 2. Large amounts of heme is released toxic to parasite Pkasmodium o Lack duffy hemokine receptor on 3. Normally, parasite polymerizes heme to non-toxic hemozoin ovale endothelial cells which transport a. Chloroquine prevents polymerization to hemozoin – parasite into human body accumulation of heme lysis of parasite & host RBC ADRs Pruritis (common) PARASITE LIFE CYCLE: Give after meals to reduce nausea and other GI symptoms 1. Anopheline (females) mosquito initiates infection Hepatic and permanent eye damage (prolonged use) CAUTIONS 2. Sporozoites invade liver Chlorouine can precipitate acute attacks of psoriasis and porphyria (hereditary blood disorder) 3. Shizonts mature in liver into then released to invade RBCs Anti-diarrheal agents (kaolin and calcium/magnesium o Hypnozoite remains dormant in liver containing antacids) interfere with absorption 4. Clinical illness 5. Gametocytes develop in RBCs before taken up by mosquitoes QUININE: DRUGS Quinine – first effective txt/reserved in cases of resistance CLINICAL PRESENTATION: Quinidine – dextrorotatory stereoisomer of quinine SYMPTOMS Symptoms result from antigens released Mefloquine – synthetic derivative ONSET from the RBCs after invasion by merozoites COMMENTS Alkaloid derived from bark of cinchona tree – used since 1820 Symptoms may appear up to ≥ 30 days after Rapidly absorbed orally, widely distributed in body tissues a trip to an area with malaria Individuals with malaria have higher plasma drug levels SYMPTOMS Fever and flu-like illness (shaking, chills, SPECTRUM Blood schizonticide against all 4 species headache, muscle aches, tiredness) Gametocidal against P. vivax and P. ovale Nausea, vomiting, diarrhea may also occur o Not active against liver stage parasites Anemia and jaundice because of loss of RBCs MOA Exact pharmacological mechanisms unknown!! IF Can result in mental confusion, seizures, ADRs UNTREATED coma, kidney failure, and death Cinchonism (tinnitus, headache, nausea, dizziness) Flushing and visual disturbances (common) Hypoglycemia (insulin release) CLASSIFICATION OF MALARIA: Hypersensitivity reactions (rash to bronchospasm) MILD Non-specific febrile illness Hematologic abnormalities (hemolytic anemia) MALARIA Terminated by antimalarial treatment or by Blackwater fever (rare), hemolysis, hemaglobinuria host responses CAUTIONS Quinine should not be given with mefloquine SEVERE 1% of cases (most are P. falciparum) Quinine can raise plasma levels of warfarin and digoxin MALARIA Severe anemia shock, ↓awareness MEFLOQUINE Caution in hepatic dysfunction, pregnancy, lactation Cerebral impairment impaired consciousness, seizures may lead to long- term neurological deficits MALARONE: Hypoglycemia, coagulopathies COMMENTS Becoming the product of choice for prophylaxis Combination of two drugs CLASSIFICATION OF ANTI-MALARIAL DRUGS: M ATOVAQUONE Tissue/blood schizonticide against all 4 species SCHIZONTICIDES Tissue – eliminate developing or O Parasite mitochondrial electron transport inhibitor dormant liver forms A Not very effective by itself against malaria Blood – act on erythrocytic parasites PROGUANIL/ Tissue/ blood schizonticide against all 4 species GAMETOCIDES Kill sexual stages and prevent PYRIMETHAMINE Selectively inhibits plasmodial dihydrofolate transmission to mosquitos reductase (key enzyme in synthesis of folate) o Don’t affect clinical symptoms Appears to synergistically enhance the effect of COMMENTS No single agent eliminates hepatic and atovaquone on mitochondrial membrane potential ABOUT ANTI- erythrocytic stages ADRs Headache and abdominal pain are possible MALARIAL DRUGS Few drugs prevent infection Can result in strange or vivid dreams Drugs prevent clinical disease CAUTION Avoid in patients with severe renal impairment No prophylaxis is fully protective Lecture 2 Pharmacology of Anti-Parasitic Drugs Kumar PHARMACOLOGY OF ANTI-MALARIALS (CONTINUED) : DOXYCLINE: RESISTANCE: COMMENTS Tetracyline antibiotic CHLOROQUINE P. falciparum (common), P. vivax (↑) SPECTRUM Blood schizonticide – all 4 strains Mutations in a putative drug transporter Not active against liver stage parasites have been suggested MOA Inhibits protein synthesis by binding to 30S ribosomal subunit Reversed by combination with certain ADRs GI symptoms (NVD) drugs (ex// chlorpheniramine) Candida vaginitis (more likely in immunocompromised pts) QUININE P. falciparum (common in some areas in Photosensitivity MEFLOQUINE South East Asia) CAUTIONS Should be given cautiously to patients with myasthenia gravis PRIMAQUINE P. vivax (New Guinea, SE Asia) o Works through acetylcholine receptors Avoid during pregnancy and children under 8 PROPHYLAXIS: o Retards skeletal bone growth BITES Prevent mosquito bites o May cause tooth discoloration o Insect repellants, insecticides, nets CARIBBEAN / Malorone or chloroquine PRIMAQUINE: C. AMERICA COMMENTS Drug of choice for eradication of dormant liver forms of BORDER AREAS High prevalence of multidrug-resistant P. vivax and P. ovale OF THAILAND falciparum malaria SPECTRUM Tissue schizonticide – all 4 strains DOXYCYCLINE Active against hypnozoite of P. vivax and P. ovale OTHER AREAS Mefloquine or malarone Gametocide – all 4 strains MOA Pharmacological mechanism unknown TREATMENT: Hydroxychloroquine is synergistic CHLOROQUINE P. malariae, vivax, ovale & falciparum ADRs Nausea, epigastric pain, abd. cramps, headache (infrequent) (non-resistant infections) Cyanosis due to hemolysis or methemoglobinemia PRIMAQUINE Used in subsequent treatment of vivax Leukopenia, agranulocytosis, leukocytosis, cardiac arrhythmias and ovale malaria to eradicate dormant CAUTIONS Avoid in granulocytopenia or methemoglobinemia hepatic stage (hypnozoite) Avoid in myelosuppressive drugs (ex// quinidine) QUININE (PO) Plus doxycycline or clindamycin Avoid in pt w/ glucose-6-phosphate dehydrogenase deficiency QUINIDINE (IV) Falciparum malaria from most areas (resistant form) PHARMACOLOGY OF ANTI-PROTOAZOALS: GIARDIASIS: AMEBIASIS: NOTES Also called “backpacker’s diarrhea” and “beaver fever” CAUSE Caused by Entamoeba histolytica o Infects a number of animal species, including beavers o Fecal-oral spread One of the most common parasite infections worldwide o Use of night soil (crop fertilization w/ human waste) Spread by fecal-oral contamination Two-stage life cycle: CAUSE Caused by Giardia lamblia 1. Cysts (infective form, shed in fees) Two-stage life cycle: 2. Trophozoites (causes disease in duodenum) 1. Cysts (infective form, shed in fees) SX 10% of world population infected but only 1/10 infected 2. Trophozoites (causes disease in duodenum) individuals get clinical disease a. Trophozoites move to colon & can spread in Symptoms 2-6 weeks post infection bloodstream to liver, lung and brain o Disrupts protective mucus layer on colonic mucosa Commonly water-borne (resistant to chlorine) and survives o Bleeding epithelial ulcerations cause colitis well in cold mountain streams ACUTE Malaise, severe abd. pain, fever, wt loss SX ACUTE Incubation period 1-2 weeks Profuse bloody diarrhea Gradual onset of long-lasting mild diarrhea CHRONIC Ameboma – collection of edematous (2-4 weeks) granulation and fibrous tissue in intestinal GI distress (nausea, vomiting, malaise, lumen pain, obstruction flatulence, cramping, steatorrhea) Liver abscesses (5 mo after infection) Significant weight loss CHRONIC Loose stool may wax and wane (months) TRICHOMONIASIS: 10-20% weight loss CAUSE Caused by Trichomonas vaginalsi Malaise, fatigue, depression Commonly sexually transmitted disease o Infects squamous epithelium of the genital tract AMERICAN TRYPANOSOMIASIS = CHAGAS DISEASE SX WOMEN 50% asymptomatic carriers CAUSE Caused by Trypanosoma cruzi Vaginal discharge, pruritis, irritation o Southern US to southern Argentina MEN Usually asymptomatic SX ACUTE Often asymptomatic Non-gonococcal urethritis & prostatitis CHRONIC 30-40% of cases – irreversible heart and GI tract lesions TREATMENT OF PROTOZOAN INFECTIONS: GIARDIASIS Metronidazole CRYPTOSPORIDIOSIS AMEBIASIS Luminal = iodoquinol CAUSE Caused by Cryptosporidium parvum Tissue = metronidazole Transmitted via fecal-oral route Liver = metronidazole then paramomycin SX Diarrhea, abd. pain and (less frequently) vomiting CHAGAS DISEASE Nitroimidazoles (ex// benznidazole) Disease is usually self-limiting (resolves in a few weeks) TRICHOMONIASIS Metronidazole Severe life-threatening disease in immunocompromised pts CRYPTOSPORIDIOSIS No effective drug treatment Lecture 2 Pharmacology of Anti-Parasitic Drugs Kumar PHARMACOLOGY
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