Treatment of malaria : Treatment of malaria Slide 2: INTRODUCTION
ETIOLOGY AND LIFE CYCLE
MALARIAL VACCINES Malaria – Early History : Malaria – Early History The symptoms of malaria were described in ancient Chinese medical writings.
In 2700 BC, several characteristic symptoms of what would later be named malaria were described in the Nei Ching. 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 :
Suppressive Prophylaxis :
Prevention of acute attack.(Kill Schizont in blood)
Clinical Cure :
Treatment of acute attack.(Rapid clearance of parasite from blood) Slide 22: Radical Cure :
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
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
Extensively bound to liver, spleen, kidney, melanin con. tissues
Metabolized in liver and excreted in urine
Half Life: 3-5 days. Loading dose?
Visual Disturbances: Keratopathy, retinopathy; ototoxicity; Neuropathy; Myopathy – on long term use.
If IV infusion- Hypotension, cardiac and resp. arrest
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
Sarcoidosis AMODIAQUINE : 28 AMODIAQUINE Action as same as chloroquine
More active against resistant strain of P. falciparum.
Combined with artemisinin
Peripheral Neuropathy QUININE : 29 QUININE Levo rotatory ,main alkaloid from bark of Cinchona tree
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.
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
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.
Nausea, vomiting, headache
Hemolysis in G6PD deficiency
Methaemoglobinaemia SULPHADOXINE + PYRIMETHAMINE : 33 SULPHADOXINE + PYRIMETHAMINE Action :
Schizonticidal, Erythrocytic stage
Mode of action:
- Dihydrofolate Reductase Inhibitor – Sequential blockade
- High affinity (2000 times) for plasmodial over mammalian enz.
Half life : 3 to 7 Days
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
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
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
- admn. orally
- Poor & Erratically absorbed
Absorption Increased by Fatty food
Half life: 3-4 Days
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
PK: admn. Orally, absorption is erratic, protein bound, excreted in feces.
T1/2: 2-3 days
-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
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
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
DOXP synthase and DOXP reductoisomerase inhibitors - fosmidomycin and FR900098.
Cysteine and aspartate proteinase inhibitor Slide 55: Glycosyl ceramide synthase
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