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Hippocrates and Malaria : Hippocrates and Malaria Hippocrates, a physician regarded as the "Father of Medicine", was the first to describe the manifestations of the disease, and relate them to the time of year and to where the patients lived. Why we need to know about malaria?Malaria Kills more people than AIDS : Why we need to know about malaria?Malaria Kills more people than AIDS Malaria kills in one year what AIDS kills in 15 years. For every death due to HIV/AIDS there are about 50 deaths due to malaria. To add to the problem is the increasing drug resistance to the established drug. Nobel Prizes in Malaria : Nobel Prizes in Malaria The discovery of parasite in mosquitoes earned the British scientist Ronald Ross the Nobel Prize in Physiology or Medicine in 1902. In 1907, Alphonse Lavern received the Nobel prize for his findings that the parasite was present in human blood. Malaria a vector borne Disease : Malaria a vector borne Disease Malaria caused by protozoan parasites. P.vivax , P.falciparum, P.ovale , P.malariae By the bite of infected female anapheles mosquito Structure of Malarial parasite : Structure of Malarial parasite LIFE CYCLE : LIFE CYCLE Asexual cycle: Man Sexual cycle: Mosquito. Man: Intermediate host Mosquito: Definitive host. Infective form: sporozoite. Malaria - Stages of the disease : Malaria - Stages of the disease Malaria the disease : Malaria the disease 9-14 day incubation period Fever, chills, headache, back and joint pain Gastrointestinal symptoms (nausea, vomiting, etc.) Periodicity can be clue in Diagnosis and species relation : Periodicity can be clue in Diagnosis and species relation Malaria tertiana: 48h between fevers (P. vivax and ovale) Malaria quartana: 72h between fevers (P. malariae) Malaria tropica: irregular high fever (P. falciparum) Malaria intensifies : Malaria intensifies Symptoms intensify Irregular high fever Anxiety, delirium and other mental problems Sweating, increased pulse rate, severe exhaustion Worsening GI symptoms Enlarged spleen and liver Malaria the disease : Malaria the disease Diagnostic Toolsfor Human Infections with Malaria : Diagnostic Toolsfor Human Infections with Malaria Blood film examination Serology - IFA PCR Thin and Thick smear : Thin and Thick smear QBC - Quantified Buffy Coat : 19 QBC - Quantified Buffy Coat The QBC Malaria method is the simplest and most sensitive method for diagnosing Heparinised tube coated with acridine Parasite DNA stained with acridine. Slide 20: 20 CHEMOTHERAPHY OF MALARIA : 21 CHEMOTHERAPHY OF MALARIA Causal Prophylaxis : Preerthyrocytic stage Suppressive Prophylaxis : Erythrocytic stage Prevention of acute attack.(Kill Schizont in blood) Clinical Cure : Erythrocytic stage Treatment of acute attack.(Rapid clearance of parasite from blood) Slide 22: Radical Cure : Exoerythrocytic cycle Complete eradication of parasite from body. (blood – tissue) Suppressive cure : Form of radical cure by extended suppressive therapy Slow action on hypnozoites by exhaustion as soon as they enter the bloodstream Gametocidal : Reduces the transmission to the mosquito ANTIMALARIAL DRUGS : 24 ANTIMALARIAL DRUGS 4-Aminoquinoline Chloroquine, Amodiaquine, Hydroxychloroquine 8-Aminoquinoline - Primaquine, bulaquine Cinchona alkaloid – Quinine Quinoline Methanol – Mefloquine Phenanthrene Methanol - Halofantrine,Lumefantrine Biguanide – Proquanil Diaminopyrimidine – Pyrimethamine Sulfonamides & sulfone: Sulfadoxine, Sulfamethopyrazine, Dapsone Sesquiterpene lactones / Endoperoxidase – Artesunate, Artemether, Arteether. Naphtoquinonqe - Atovaquone Antibiotics - Tetra, Doxy, Macrolide Aims and objectives of treatment : Aims and objectives of treatment CHLOROQUINE : 26 CHLOROQUINE Blood Schizonticidal Gametocidal on ovale, vivax and malariae PK: - Basic in nature Oral-IM-IV infusion Vd large Extensively bound to liver, spleen, kidney, melanin con. tissues Metabolized in liver and excreted in urine Half Life: 3-5 days. Loading dose? Adverse effects: G.I. Disturbances Visual Disturbances: Keratopathy, retinopathy; ototoxicity; Neuropathy; Myopathy – on long term use. If IV infusion- Hypotension, cardiac and resp. arrest CI: Safe for children and in pregnancy Not in G6PD D, psoriasis, porphyria, liver diseases. MOA and other uses : MOA and other uses Extra intestinal amoebiasis RA DLE Lepra r/n Photogenic r/n IM Sarcoidosis AMODIAQUINE : 28 AMODIAQUINE Action as same as chloroquine More active against resistant strain of P. falciparum. Combined with artemisinin Toxicity Agranulocytosis Hepatotoxicity Peripheral Neuropathy QUININE : 29 QUININE Levo rotatory ,main alkaloid from bark of Cinchona tree Action : Erythrocytic schizonticidal - PV, PF. Gametocyte of P. vivax and P. ovale Mode of Action : Gets concentrated in the acidic vacuoles of blood schizonts & causes pigment changes Inhibits polymerization of heme to hemozoin Accumulation of Haem - cytotoxic Half Life : 11-18 hrs. QUININE(contd..) : 30 QUININE(contd..) Adverse effects : Gl disturbances, bitter taste Cinchonism – tinnitus, deafness, vertigo, nausea, vomiting, dysphoria CV : Hypotension, Arrhythmia, Prolongation QT interval. Neurotoxic Stimulate pancreas ↑ insulin – Hypoglycemia Blackwater fever: Haemolysis -renal failure-death Other uses: Drug interactions: - Nocturnal leg cramps - warfarin - Babesiosis - digoxin Varicose veins MEFLOQUINE : 31 MEFLOQUINE Action : Schizonticidal – Mature Trophozoite, schizont. Mode of action : Similar to Quinine Half life : 3 weeks Toxicity Nausea, Vomiting, Dizziness Orthostatic Hypotension, abnormal AV conduction Neuro-psychiatric reaction(Convulsion, Psychosis, Encephalopathy) PRIMAQUINE : 32 PRIMAQUINE Action : Erythrocytic stage of parasite – Acute stage Hypnozoite of P.vivax (prevent relapse) Gametocyte of P.falciparum (prevent transmission) Mode of action : - Disrupts mitochondrial ETC of the parasite Generates reactive oxygen free radicals Half life: 3-6 hrs. Toxicity : Nausea, vomiting, headache Visual disturbances Hemolysis in G6PD deficiency Methaemoglobinaemia SULPHADOXINE + PYRIMETHAMINE : 33 SULPHADOXINE + PYRIMETHAMINE Action : Schizonticidal, Erythrocytic stage Sporonticidal action Mode of action: - Dihydrofolate Reductase Inhibitor – Sequential blockade - High affinity (2000 times) for plasmodial over mammalian enz. Half life : 3 to 7 Days Toxicity : Megaloblastic Anaemia, Bone Marrow Depression Sulpha drug: Skin rash, Hepatitis, Steven Johnson’s Syndrome Methhaemoglobinemia PROGUANIL : PROGUANIL Biguanide Action similar to pyrimetamine Prodrug : converted to cycloguanil Used with combining Atovaquone (malarone) ARTEMISININ DERIVATIVES : 36 ARTEMISININ DERIVATIVES 2000 yrs. Old Chinese medicine - QUINGHAOSU Rediscovered in 1971 – used since 1987 Artemisinin Arteether Artemether Artesunate MOA : MOA Artemisinin is a cyclic endoperoxide compound that forms a free radical after activation by iron (Fe). This free radical is able to alkylate macromolecules such as heme and proteins, resulting in the formation of artemisinin-heme adducts and artemisinin-protein adducts that are toxic to plasmodia. ARTESUNATE : 38 ARTESUNATE PK: IV, IM, Oral, Rectal. Metabolite: Dihydroartemisinin (active) Half life: <1hr Toxicity : Nausea, Vomiting, Itching, Dizziness, Occ convulsion Interaction : Potentiates the action of Mefloquine,Primaquine & Tetracyclines Additive Effect with Chloroquine Antagonistic Effect with Sulpha-Pyrimethamine. HALOFANTRINE : 39 HALOFANTRINE More potent than Quinine,Mefloquine Action: inhibits the plasmodium proton pump PK: - admn. orally - Poor & Erratically absorbed Absorption Increased by Fatty food Half life: 3-4 Days Toxicity : Gl. disturbances, Diarrhoea Cardiac Arrhythmia, Prolonged QT interval Sudden death due to VT Embryotoxic in animal studies ATOVAQUONE : ATOVAQUONE Structural analogue of ubiquone Used in combination with proguanil ( malarone) PK: admn. Orally, absorption is erratic, protein bound, excreted in feces. T1/2: 2-3 days Other uses: -P. Carnii -T. gondii AtovaquoneMOA: interacts with ubiquone and cyt bc1, distrupts the MET- Complex 3 of resp. chain, inhibits ATP synthesis : AtovaquoneMOA: interacts with ubiquone and cyt bc1, distrupts the MET- Complex 3 of resp. chain, inhibits ATP synthesis ANTIBIOTICS WITH ANTIMALARIAL ACTIVITY : 42 ANTIBIOTICS WITH ANTIMALARIAL ACTIVITY Tetracyclines, Doxycycline : Slow Schizonticidal used with Quinine, Primaquine Macrolides – Azithromycin, Clarithromycin, Clindamycin Rifampicin Quinolone – Norfloxacilin, Ciprofloxacilin CHEMOPROPHYLAXIS : CHEMOPROPHYLAXIS For short-term chemoprophylaxis (less than 6 weeks) Doxycycline: 100 mg daily in adults and 1.5 mg/kg for children more than 8 years old. The drug should be started 2 days before travel and continued for 4 weeks after leaving the malarious area For long-term chemoprophylaxis (more than 6 weeks) Mefloquine: 5 mg/kg B.wt (up to 250 mg) weekly and should be administered two weeks before, during and four weeks after leaving the area. Treatment of Uncomplicated malaria : Treatment of Uncomplicated malaria Artemisinin combined therapy : Artemisinin combined therapy Artemether-lumefantrine Co-formulated tablets: 20 mg artemether + 120 mg lumefantrine BD × 3 days Should be taken with milk/fat containing foods Artesunate + mefloquine Separate tablets:50 mg artesunate, 250 mg base mefloquine 4 mg/kg of artesunate OD × 3 days, 25 mg base/kg of mefloquine usually split over 2 or 3 days (15 mg/kg usually on the second day followed by 10 mg/kg one day later Artesunate + sulfadoxine–pyrimethamine Separate tablets:50 mg artesunate, 500 mg of sulfadoxine + 25 mg of pyrimethamine. 4 mg/kg artesunate OD × 3 days and a single administration of sulfadoxine-pyrimethamine 25/1.25 mg base/kg on day 1 Artesunate + amodiaquine Separate tablets:50 mg of artesunate, 153 mg base of amodiaquine 4 mg/kg artesunate and 10 mg base/kg of amodiaquine OD × 3 days Slide 49: 49 Recrudescence. The recurrence of asexual parasitaemia after treatment of the infection with the same species that caused the original illness. Incomplete clearance of parasitaemia by treatment. Relapse. The recurrence of asexual parasitaemia in P. vivax and P. ovale malaria deriving from persisting liver stages (hypnozoites). Recurrence. The recurrence of asexual parasitaemia following treatment. This can be caused by Recrudescence Relapse New infection. Treatment of complicated and severe malaria Parenteral Artemisinin derivatives or quinine should be used irrespective of chloroquine sensitivity : Treatment of complicated and severe malaria Parenteral Artemisinin derivatives or quinine should be used irrespective of chloroquine sensitivity Treatment of malaria in children : Treatment of malaria in children Similar to adults Quinine – better tolerated in children. But, caution while using it parenterally due to its toxicity Chloroquine- when given parenterally convulsions occur. Therefore avoid its use. In relapse, use pyrimethamine 12.5 mg once weekly b/w the attacks. Treatment of Malaria in Pregnancy : 52 Treatment of Malaria in Pregnancy In first trimester of pregnancy, parenteral quinine is the drug of choice. However, if quinine is not available, artemisinin derivatives may be given to save the life of mother. In second and third trimester, parenteral artemisinin derivatives are preferred. Treatment of Vivax Malaria in Pregnancy : Treatment of Vivax Malaria in Pregnancy Use of Primaquine & Proguanil are not safe in pregnancy and also in lactating mothers. Therefore to prevent the relapse of vivax malaria, suppressive chemoprophylaxis with Chloroquine is recommended. Tablet Chloroquine 300 mg (base) weekly should be administered to all such patients until stoppage of lactation. At that point, a complete treatment with full therapeutic dose of Chloroquine and Primaquine (7.5mg b.d. or 15mg daily, for 14 days) should be administered. However in case of resistance, Primaquine or Proguanil may be given with caution in 2nd half of pregnancy. Radical cure NEW ANTIMALARIAL STRATEGIES : NEW ANTIMALARIAL STRATEGIES Pyonaridine Piperaquine Proteosome inhibitor-Lactacystin DOXP pathway: DOXP synthase and DOXP reductoisomerase inhibitors - fosmidomycin and FR900098. Cysteine and aspartate proteinase inhibitor Slide 55: Glycosyl ceramide synthase L-malate dehydrogenase Chalcones and flavonoids therapy WR238605 - tafenpquine Use of antisense nucleotides and reverse transcriptase inhibitors of P. falciparum telomerase. Malarial vaccines : Malarial vaccines World Malaria Day, April 25 : World Malaria Day, April 25 April 25 is World Malaria Day, which commemorates the date in 2000 when 44 African leaders committed to cutting malaria deaths in half by 2010. Goal of Medical Humanity : Goal of Medical Humanity THANK YOU : 60 THANK YOU You do not have the permission to view this presentation. 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