MANAGEMENT OF CHLOROQUINE RESISTANT MALARIA BY Dr.HARMANJIT SINGH , DEPARTMENT OF PHARMACOLOGY, GMC, PATIALA
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MANAGEMENT OF CHLOROQUINE RESISTANT MALARIA BY Dr.HARMANJIT SINGH , DEPARTMENT OF PHARMACOLOGY, GMC, PATIALA

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MANAGEMENT OF CHLOROQUINE RESISTANT MALARIA BY Dr.HARMANJIT SINGH , DEPARTMENT OF PHARMACOLOGY, GMC, PATIALA MANAGEMENT OF CHLOROQUINE RESISTANT MALARIA BY Dr.HARMANJIT SINGH , DEPARTMENT OF PHARMACOLOGY, GMC, PATIALA Presentation Transcript

  • MANAGEMENTOF CHLOROQUINE RESISTANT MALARIA
    Dr.HARMANJIT SINGH
    JR- PHARMACOLOGY
    GMC , PATIALA
  • CONTENTS
    Introduction
    Life cycle
    Anti malarial drugs
    Treatment (Chloroquine sensitive & Resistant both)
    Anti malarial vaccine
    Summary
    2
  • MALARIA
    • Malaria was once considered to arise from marshy land (hence the name 'mal aria'-bad or poisonous air)
    • Caused by : Plasmodium.
    • Four species : P.vivax,
    • P.falciparum,
    • P.ovale
    P.malariae.
    The insect vector : female Anopheles mosquito
    • Breeds in stagnant water.
  • MALARIA
    • Malaria remains the world’s most devastating human parasitic infection, afflicting more than 500 million people and causing from 1.7 million to 2.5 million deaths each year.
    • In 2010, more than 100 countries were considered malarious.
    • Malaria kills more than 1 million children a year in the developing world
    • In malaria endemic areas - Children under age of 5 years - greater risk of dying
  • Malaria Endemic Areas
    Chloroquine resistant-PF
    Chloroquine sensitive-PF
    Mexico, Central America west of Panama canal,
    Carribean, South America, middle east
    Resistant PV
    Indonesia,Papua New Guinea, Burma
  • DRUG RESISTANT MALARIA
    Definition: Drug resistance is the ability of the parasite species to survive and/or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within the limit of tolerance.
    MDR Malaria
    Resistance to 3 or more anti-malarials of different chemical classes of which two are
    4-aminoquinolines and diaminopyrimidine”
    7
  • Resistance occurs most commonly due to improper treatment and inadequate dosage of antimalarials
    The important factors that are associated with resistance are:
    1. Longer half-life. 2. Single mutation for resistance. 3. Poor compliance 4. Host immunity. 5. Number of people using these drugs.
    Although chloroquine resistant strains of P. vivax have been described, drug resistance poses a serious clinical problem only with P. falciparum: >70% of cases
    8
  • Global Scenario of Drug Resistant Malaria
    P. falciparum resistance
    􀁺 Chloroquine resistant strains are found now in nearly all areas of chloroquine use including South America, Central America, east of the Panama Canal, the Western Pacific, East Asia
    P. vivax resistance
    􀁺 Recent reports from Indonesia (Irian Jaya, Sumatra) and Papua, New Guinea indicate high levels of P. vivaxschizonts resistant to chloroquine. Decreased susceptibility may also be appearing in the Solomon Islands, Myanmar, Brazil, Colombia.
    P. ovale and P. malariae resistance
    􀁺 P. ovale and P. malariae forms have not shown resistance to chloroquine
    9
  • MECHANISM
    Resistant strains are able to efflux the drug by an active pump mechanism and, thereby rendering the drug ineffective.
    Resistant strains concentrate chloroquine less in vacuoles.
    Crt-Chloroquine resistant transporter and Pfmdr transporters : mutations
    There is an increase in the surface area of the resistant parasites, permitting more efficient pinocytosis.
    Binding of chloroquine with haemoglobin breakdown product to form toxic complexes is also prevented.
    Nonspecific pump inhibitors like calcium channel blockers or antagonists of calmodulin (e.g. verapamil), have not shown any benefit
    10
  • Types of Drug Resistance
    􀁺 In defining criteria for resistance to the aminoquinolineantimalarial drugs, the WHO has described three grades of resistance following treatment
    􀁺 (Low grade) R1 : Recrudescence of infection between 7 and 28 days of completing treatment following initial resolution of symptoms and parasite clearance.
    􀁺 (High grade) R2 : Reduction of parasitaemia by > 75% at 48 hours but failure to clear parasites
    within 7 days.
    􀁺 R3 : Parasitaemia does not fall by >75% within 48 hours.
    11
  • Indian Scenario of Drug Resistant Malaria
    P. falciparum >> P. vivax
    Incidence being 5% to full dose chloroquine
    The first confirmed report of chloroquine resistance in P. falciparum was reported in Diphuarea of Karbianglong district of Assam in 1973.
    Resurgence of P. falciparum resistant to chloroquine has been noticed in several regions of India, more in North Eastern parts of the country
    KEM hospital in Mumbai, confirmed the existence of chloroquine resistance in P. falciparum cases in Mumbai
    However for all practical purposes, drug resistant malaria in the Indian context means malaria caused by strains of P. falciparum which are resistant to chloroquine.
    12
  • Clinical features
    Cold Stage
    • Feeling of Intense Cold
    • Vigorous Shivering, Rigor
    • Lasts 15-60 Min
    Hot Stage
    • Intense Heat
    • Dry Burning Skin
    • Throbbing Headache
    • Lasts 2-6 Hours
    Sweating Stage
    • Profuse Sweating
    • Declining Temperature
    • Exhausted, Weak
    • Lasts 2-4 Hours
    13
  • Why P.F. Serious?
    Binds-RBCs all ages
    Alters surface
    Grows in low o2
    Micro-vascular blocks
    Cytokine release
    Endotoxin release
    High parasitemia
    Cerebral malaria
    Hypoglycemia
    Shock, Multi organ failure
    Death
    P.Palciparum
    Produces
    Leads to
  • Diagnosis
    Thick Smear : Rapid Diagnosis
    Thin: Species identification
    Rapid diagnostic test
    Antibody detection test- RIA - ELISA
    15
  • 1. Chemical classification
    . 4-aminoquinolines:
    - Chloroquine, amodiaquine, Piperaquine
    8-aminoquinolines: - Primaquine , Bulaquine
    Folate synthesis inhibitors:
    - Sulphonamides like Sulphadoxine , Dapsone
    - Biguanides like proguanil and chloroproguanil
    -Diaminopyrimidine like pyrimethamine
    CINCHONA ALKALOIDS : Quinine , Quinidine
    AMINO ALCOHOLS : - Lumefantrine , Halofantrine
    -
    16
  • Antimicrobials: 
    Tetracycline, doxycycline, clindamycin, azithromycin, fluoroquinolones ,FOSMIDOMYCIN
    Peroxides:
    Artemisinin(Qinghaosu) derivatives and analogues - artemether, arteether, artesunate, artelinic acid
    Naphthoquinones:
    Atovaquone
    Iron chelating agents:
    Desferrioxamine
    Chemical classification
    17
  • 2. According To Mode Of Action
    FOR CAUSAL PROPHYLAXIS
    MODE : Pre-erythorcyticSchizonticides ( kill schizonts in the liver )
    DRUGS :
    - Primaquine
    - Proguanil
    - Tetracycline
    FOR THE TREATMENT OF ACUTE ATTACK
    MODE : ErythrocyticSchizonticides (kill schizonts in the Blood)
    DRUGS :
    • Rapidly acting : - Chloroquine, quinine , atovaquone , artemisinin derivatives, mefloquine
    • Slow acting :-
    • Proguanil, sulphonamides , tetracyclines , pyrimethamine
    18
  • According To Mode Of Action
    FOR PREVENTION OF TRNSMISSION
    MODE : GAMETOCIDES ( kill Gametes )
    DRUGS :
    - Primaquine : for all species
    - Artemisinin : for all
    - Quinine : For vivax
    - Chloroquine : for vivax
    FOR RADICAL CURE
    MODE : Exo-erythrocyticSchizonticides (killExo-erythrocytic forms i.e. Hypnozoites)
    DRUGS :
    - Primaquine
    19
  • Site of action
    20
  • CHLOROQUINE
    Erythrocytic schizontocide: all plasmodial species
    Gametocytic: not P.falciparum
    No effect on sporozoites, hypnozoites
    MOA: Concentrates in parasite food vacuoles, ↑pH
    Disruption of polymerization of Heme to Hemozoin
    Heme damage plasmodium membrane
    • Well absorbed: oral, IM, SC .60% PPB
    Metabolized by liver , t1/2: 3-10 days
    Excreted by kidney.
    21
  • Chloroquine
    ADRs:Nausea, vomiting, Blurring of vision ,Headache, Confusion, seizures
    Hemolysis: G6PD individuals, Impaired hearing
    Hypotension, ECG changes
    High dose: Irreversible ototoxicity, retinopathy, myopathy, Peripheral neuropathy
    Chloroquine sulphate (Tab)136 mg = 100 mg Base
    Chloroquine phosphate (Tab) 250mg=150mg Base
    Dose : 600 mg stat , 300 mg after 8 hours and then for next two days
    22
  • Faster acting
    MOA & resistance similar to chloroquine
    ADRs
    Toxic hepatitis
    Agranulocytosis
    Dose: 25-35 mg/kg over 3 days
    Chloroquine resistant: combine Artesunate
    Amodiaquine
    23
  • Mefloquine
    Erythrocytic schizontocide
    Rapidly control fever, eliminate circulating parasite
    Effective: Chloroquine resistant plasmodium
    MOA:- Inhibits heme polymerization
    - Forms toxic complexes with free heme
    Oral absorbed ,Highly protein bound ,Extensive tissues distribution
    ADRs Nauses, Vomiting, Diarrhoea
    Neuropsychiatric
    Arrythmias , Haematological
    Hepatic toxicity
    Dose:1250 mg, 750 mg, 500mg 12 hrly
    24
  • Quinine
    Derived from bark of cinchona tree
    Effective blood schizonticidal
    Gametocidal: P. vivax
    Chloroquine resistant
    MDR FP
    MOA: same as of chloroquine
    Oral absorption rapid & complete ,Bound to α1 acid glycoprotein , Metabolized by CYP3A4 ,Excreted in urine t1/2: 10-12 hrs
    25
  • Quinine
    ADRs :Cinchonism:tinnitus,dysphoria, headache, Nausea, vomiting, dizziness, flushing & visual disturbances,
    GIT: nausea, vomiting, diarrhoea,abdominal pain
    Hypoglycemia
    CVS: hypotension, dysrhythmias, VT, fibrillation
    Hemolysis (G6PD deficiency)
    Blackwater fever: hemolysis, hemoglobinemia, hemoglobinuria.
    Dose:
    Quinine: 600 mg 8 hrly
    26
  • Pyrimethamine
    Erythrocytic schizontocide
    Resistance develops rapidly if used alone
    MOA : DHFRase inhibitor
    Oral: absorption good, slow
    Concentrated: liver, spleen, kidneys
    Metabolized: liver ,Excreted: renal & t1/2: 4 days
    ADRs : Nausea, Rashes, Folate deficiency
    Dose: sulphadoxine 1500 mg
    +
    pyrimethamine 75 mg
    27
  • Proguanil
    Erythrocyte schizontocide
    Cyclic triazine metabolite: cycloguanil
    MOA: DHFRase Inhibitor
    Slowly, adequately absorbed ,Partly metabolized
    Excreted in urine & t1/2 is 20 hrs.
    ADRs : Vomiting, Abdominal pain ,Haematuria
    Dose: 200-300 mg/day for 4wks
    28
  • Primaquine
    Radical cure of relapsing cases
    Preerythrocytic Gametocytes & hypnozoites
    MOA : - Interferes electron transport of parasite
    Readily absorbed orally, oxidized in liver
    t1/2: 3-6 hrs ,excreted in urine
    ADRs : Abdominal pain, GI upset Hemolysis in G6PD deficiency, methaemoglobinaemia
    Dose: 15 mg/day for 2wks
    29
  • Sulphonamides
    Blood schizonticides
    Given in combination
    MOA: inhibit folatesynthetase
    Oral: Rapidly absorbed ,Metabolized by acetylation in liver ,Excreted by kidneys
    Dose : (Chloroquine resistant P.falciparum)
    sulphadoxine 1500 mg + pyrimethamine 75 mg
    30
  • Tetracyclines
    Week erythrocytic schizonticidal
    Use with Quinine, S/P
    Multidrug resistant cases .
    31
  • FOSMIDOMYCIN
    Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, an essential enzyme of the nonmevalonate pathway
    fosmidomycin blocks the biosynthesis of isopentenyldiphosphate and the subsequent development of isoprenoids in P. falciparum .
    In contrast, isoprenoids are derived from an alternative pathway, known as the mevalonate pathway, in mammals .
    Hence, fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids, which are essential for cellular function,
    32
  • Artemether, Artesunate, Arteether
    Blood schizonticidal
    Duration of action short, recrudescence rate high
    Combine with a long acting drug
    Artemisinin derivatives
    33
  • MOA
    Endoperoxide bridge interact haeme of parasite
    Release highly reactive free radicals
    Damage membrane protein
    Inhibits protein synthesis
    Lysis of parasite
    Artemisinin derivatives
    34
  • PKs
    Artemisinin derivatives
    35
  • ADRs:
    Nausea, Vomiting
    Abnormal bleeding
    ST segment changes, QT prolongation
    Artemisinin derivatives
    36
  • Artesunate-mefloquine
    100 mg BD for 3 days + 750 mg 1st day, 500 mg 2nd day
    Aretemether-lumefantrine
    80 mg + 480 mg BD for 3 days
    Artesunate-sulfadoxine+pyrimethamine
    100 mg BD for 3 day + 1500 mg & 75 mg single dose
    ACT regimens for uncomplicated falciparum malaria
    37
  • Halofantrine
    Blood schizontocide
    Effective: chloroquine & S/P resistant
    PKs
    Oral absorption: low
    t 1/2: of active metabolite 3 day
    ADRs
    Cardiovascular toxicity
    38
  • Atovaquone
    Erythrocytic schizontocide
    MOA: Mitochondrial electron transport
    Interferes ATP production
    PKs : Lipid soluble: absorption slow
    99% bound plasma proteins
    Enterohepatic circulation
    t1/2: 1.5-3 days
    Dose:Atovaquone: 250 mg & Proguanil: 100mg for 3 days
    ADRs
    Vomiting, diarrhoea
    Maculopapular rash
    39
  • Chemoprophylaxis: Indications
    Special risk groups:
    Non-immune travellers
    Non-immune persons living in endemic areas
    Pregnancy- After 1st trimester (Chloroquine, Proguanil, Quinine)
  • Chemoprophylaxis
  • Prophylaxis in Pregnancy
    Travellers
    Avoid travel[Pregnant or likely to become pregnant!!]
    Chlo or Proguanil+F.A
    Or Meflo in II, III trimester
    Doxy, Atova, Prima : C/ I.
    Mosquito net
    Intermittent Preventive Treatment [IPT]:
    Pregnant in endemic areas
    Pyr+Sulfa
    2-3 doses
    I dose after quickening-II trimester
    Further at 1 month intervals
  • Sulfadoxine-pyrimethamine (SP): effective drug for IPT
    S/P
    500 mg of sulfadoxine
    25 mg of pyrimethamine
    Malaria During Pregnancy
    43
  • Treatment-Chloroquinesensitive:P.V.
    Chloroquine po4 1 Tab=250mg salt or 150mg base
    Clinical cure- 0h - 4Tab stat
    6h - 2 Tabs
    24h - 2 Tabs
    48h - 2 Tabs
    Radical cure: Primaquine 15mg/d X 14 days. Primaquine C.I in G6PD def.
  • Treatment-ChloroquineResistant:P.V.[Rare]
    Quinine 600mg 8thhrly X 7 days
    +
    Doxy 100mg daily X 7 days
    +
    Primaquine 15 mg x 14 days
  • Treatment-ChloroquineSensitive:FP
    Chloroquine Phoshphate :[250mg] = 150mg Base
    0h - 4Tab stat
    8h - 2 Tabs
    24h - 2 Tabs
    48h - 2 Tabs
    +
    Primaquine 45 mg single dose[gametocidal]
    OR
    Sulfadoxine/Pyrrimethamine 3 Tab + Primaquine[Chlo not tolerated]
  • Treatment-ChloroquineResistant:FP
    Artesunate 100mg BDx3days + Sulfadoxine/Pyrimethamine 1500/75 mg (3 tab single dose)
    OR
    Mefloquine 750mg on 2nd day-500mg on 3rd day.
    Artemether 80mg + Lumefantrine 480mg BD x 3 days
    Quinine 600mg 8thhrly x 7 days + Doxycycline 100mg daily x 7 days
  • Severe malaria
    Cerebral malaria:
    Severe anemia
    Renal failure
    Pulmonary edema
    Shock
    Metabolic acidosis
    Hemoglobinuria, jaundice
    Hyperpyrexia
    Hyperparasitemia
    The single most important step in the management of severe malariais IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
  • Severe and complicated F.P.Malaria
    Artesunate 2.4mg/Kg i.v or i.m. » 12 hrs » 24 hrs » OD x 7days [Change to oral ACTx3days, if possible]
    Or
    Artemether: 3.2mg/Kgi.m on 1st day and then 1.6mg/Kg x 7days [change to oral ACTx3days, if possible ]
    Or
    Arteether: Same as above. But 4 days
    Or
    Quinine diHCL:20mg/Kg in 10ml/Kg of 5% dextrose infused 4hrs » 10mg/Kg for 4hrs every 8hrs » Oral quinine10mg/kg tds x7days
    + doxy 100mg od oral or 3day oral ACT or pyrimethamine/Sulfadoxine
  • Treatment-Severe malaria
    Quinidinegluconate-
    10mg/kg in 300ml of N.S over 2-3h (max600mg)

    0.02mg/kg/.min infusion for 24 h

    Oral quinine sulfate 600mg tid X 7 days
    AND Adjunctive therapy oral
    Doxy 100mg bd
    or
    Clindamycin 20mg/kg/day X 7days
    or
    Pyr+Sulfa 3 tab on last day of quinine
  • PREVENTION OF RESISTANCE
    Selection of drugs - Use conventional drugs first in uncomplicated cases. Greater the exposure, higher will be the emergence of resistance.
    Avoid drugs with longer half-life if possible.
    Avoid basic antimalarials for non-malarial indications (e.g. Chloroquine for rheumatoid arthritis in a malarial endemic area).
    Ensure compliance.
    Monitoring for resistance and early treatment of these cases to prevent their spread.
    Clear policy of using newer antimalarials.
    Use of combinations to inhibit emergence of resistance.
    51
  • Malaria Vaccine
    Reduce severity and complications of malaria
    Tried in children less than 5yrs, in Africa
    Reduces mortality and morbidity
    RTS,S/AS01,
    Phase III
    Potential targets of the vaccine
    pre-erythrocytic
    erythrocytic
    merozoite
    gametocyte
  • Newer regimens under development
    1.Dihydroartemisinin-Piperaquine
    120 mg + 960 mg daily for 3 days
    2. Artesunate-amodiaquine
    200 mg + 600 mg daily for 3 days
    3. Astesunate-pyronaridine
    200 mg + 600 mg daily for 3 days
    4. Arterolane (RBx 11160)-piperaquine
    5. Artesunate-chlorproguanil + Dapsone
    6. Fosmidomycin + Clindamycin
    53
  • SUMMARY :
    Drug resistant malaria is a serious problem worldwide
    P.falciparum should be treated with artemisinin derivatives
    Chemoprophylaxis should be followed wherever appropriate
    Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups e.g. travelers
    For Severe Malaria cases Parenteral therapy should be given
    Drug combinations should be used
    54
  • THANK YOU
    55