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Antimalarial drugs
Plasmodium species which
          infect humans


Plasmodium vivax (tertian):
Plasmodium ovale (tertian)
Plasmodium falciparum (tertian)
Plasmodium malariae (quartan)

Plasmodium knowlesi:
Sir Ronald Ross
Life cycle of the malarial parasite
                             True causal prophylactics
       Sporonticide                                      Schizogony
     Sporogeny                                           (asexual)
     (sexual)
                                                            Causal
                                                            prophylactics

                                                            Supressives



Man : Intermediate host
Mosquito : Definitive host                           Gametocidal
• Classification of antimalarial drugs
  – Therapeutic classification
  – Chemical classification
Therapeutic classification

• Causal prophylaxis: (Primary tissue
  schizonticides)
  – Destroy parasite in liver cells and prevent invasion of
    erythrocytes
  – Primaquine, proguanil
• Supressives Prophylaxis:
  – Supress the erythrocytic phase and thus attack of
    malarial fever can be used as prophylactics
  – Chloroquine, proguanil, mefloquine, doxycycline
Therapeutic classification

• Clinical cure: erythrocytic schizonticides
  – used to terminate an episode of malarial fever
• Fast acting high efficacy
  – Chloroquine, quinine, mefloquine, atovaquone,
    artemisinin
• Slow acting low efficacy drugs
  – Proguanil, pyrimethamine, sulfonamides,
    tetracyclines
Therapeutic classification
• Radical curatives:
  – Eradicate all forms of P.vivax & P.ovale from the body
  – Supressive drugs + hypnozoitocidal drugs
  – For vivax: primaquine 15 mg daily for 14 days
• Gametocidal:
  – Destroy gametocytes and prevent transmission
  – Primaquine, artemisinin – against all plasmodia
  – Chloroquine, quinine – Pl Vivax
  – Proguanil ,pyrimethamine – prevent development
    of sporozoites
Chemical classification
• 4 aminoquinolines:
  – Chloroquine, Hydroxychloroquine, Amodiaquine, Pyronari
    dine
• 8 aminoquinolines:
  – Primaquine, Tafenoquine, Bulaquine
• Cinchona alkaloids:
  – Quinine, Quinidine
• Quinoline methanol:
  – Mefloquine
• Biguanides
  – Proguanil, Chlorproguanil
Chemical classification
• Diaminopyrimidines
  – Pyrimethamine
• Sulfonamides
  – Sulfadoxine, dapsone
• Tetracyclines:
  – tetracycline, doxycycline
• Naphthoquinone:
  – Atovaquone
• Sesquiterpene lactones:
  – Artesunate, artemether, arteether
• Chloroquine:
  – Synthesized by Germans in 1934 ( resochin)




  – d & l isomers, d isomer is less toxic
  – Cl at position 7 confers maximal antimalarial
    efficacy
Mechanism of action
            Hemoglobin            Globin utilized by
                                  malarial parasite

             Heme (highly toxic for malaria parasite)
Chloroquine
Quinine,                 (+) Heme Polymerase
mefloquine (-)

             Hemozoin (Not toxic to plasmodium)
Pharmacological actions
1. Antimalarial activity:
  –   High against erythrocytic forms of
      vivax, ovale, malariae & sensitive strains of
      falciparum
  –   Gametocytes of vivax
  –   No activity against tissue schizonts
  –   Resistance develops due to efflux mechanism
2. Other parasitic infections:
  –   Giardiasis, taeniasis, extrainstestinal amoebiasis
3. Other actions:
  –   Depressant action on myocardium, direct relaxant
      effect on vascular smooth
      muscles, antiinflammatory, antihistaminic , local
Pharmacokinetics
• Well absorbed, tmax 2-3 hrs , 60 % protein
  bound
• Concentrated in liver , spleen, kidney, lungs ,
  leucocytes
• Selective accumulation in retina: occular
  toxicity
• T1/2 = 3-10 days increases from few days to
  weeks
Adverse drug reactions
• Intolerance:
  – Nausea, vomiting, anorexia
  – skin rashes, angioneurotic edema,
    photosensitivity, pigmentation, exfoliative
    dermatititis
  – Long term therapy may cause bleaching of hair
  – Rarely thrombocytopenia, agranulocytosis,
    pancytopenia
Adverse drug reactions
• Occular toxicity: High dose prolonged therapy
  – Temporary loss of accommodation
  – Lenticular opacities, subcapsular cataract
  – Retinopathy: constriction of arteries, edema, blue
    black pigmentation , constricted field of vision.
• CNS:
  – Insomnia, transient depression seizures,
    rarely neuromyopathy & ototoxicity
• CVS:
  – ST & T wave abnormalities, abrupt fall in BP &
    cardiac arrest in children reported
Dosage
• 600 mg of base stat
• 300 mg base after 8 hours
• 150 mg of base BD for 2 days



• 200 mg oral tablet of chloroquine phosphate
  consists of 150 mg base
Chloroquine is administered in loading
          dose in malaria
• Chloroquine is well absorbed after oral
  administration. It is extensively tissue bound
  and sequestrated by tissues particularly
  liver, spleen, kidney it has got large apparent
  volume of distribution
• So it is given in loading dose to rapidly achieve
  the effective plasma conc.
Therapeutic uses
1.   Hepatic amoebiasis:
2.   Giardiasis
3.   Clonorchis sinensis
4.   Rheumatoid arthritis
5.   Discoid Lupus Erythematosus
6.   Control manifestation of lepra reaction
7.   Infectious mononucleosis
• Hydroxy chloroquine:
   – Less toxic, properties &uses similar
• Amodiaquine:
   – As effective as chloroquine
   – Pharmacological actions similar
   – Chloroquine resistant strains may be effective
   – Adverse events: GIT, headache
     , photosensitivity, rarely agranulocytosis
   – Not recommended for prophylaxis
• Pyronaridine: effective in resistant cases
Quinine
• 1820 Pelletier & caventou isolated quinine
  from cinchona bark.
• Mechanism of action:
  – Similar to chloroquine
Pharmacological actions
1. Antimalarial action:
  –   Erythrocytic forms of all malarial parasites including
      resistant falciparum strains .
  –   Gametocidal for vivax & malariae
2. Local irritant effect:
  –   Local pain sterile abcess.
3. Cardiovascular:
  –   depresses myocardium, ↓ excitability, ↓ conductivity,
      ↑ refractory period, profound hypotension IV.
4. Miscellaneous actions:
  –   Mild analgesic, antipyretic activity , stimulation of
      uterine smooth muscle, curaremimitic effect
Adverse drug reactions
Cinchonism:
• Tinnitus, nausea & vomiting
• Headache mental confusion, vertigo,
  difficulty in hearing & visual disturbances
• Diarrhoea , flushing & marked perspiration
• Still higher doses , exagerated symptoms
  with delirium , fever, tachypnoea,
  respiratory depression , cyanosis.
Adverse drug reactions
• Idiosyncrasy : similar to cinchonism but
  occurs in therapeutic doses
• Cardiovascular toxicity: cardiac
  arrest, hypotension ,fatal arrhytmias
• Black water fever:
• Hypoglycemia:
Uses
• Malaria:
  – uncomplicated resistant falciparum malaria
  – Cerebral malarial
• Myotonia congenita: 300 to 600 mg BD/ TDS
• Nocturnal muscle cramps: 200 – 300 mg
  before sleeping
• Spermicidal in vaginal creams
• Varicose veins: along with urethane causes
  thrombosis & fibrosis of varicose vein mass
• Primaquine:
  – Mechanism of action:


  Primaquine

    Converted to
    electrophiles

        Generates reactive
        oxygen species

  – Interferes with oxygen transport system
Antimalarial action
• Liver hypnozoites
• Weak action against erythrocytic stage of
  vivax, so used with supressives in radical cure
• No action against erythrocytic stage of
  falciparum
• Has gametocidal action and is most effective
  antimalarial to prevent transmission disease
  against all 4 species
Adverse effects

• Gastrointestinal:
  – epigastric
    distress, abdominal cramps ,
• Hemopoetic:
  – mild
    anemia, methaemoglobinem
    ia, cyanosis, hemolytic
    anemia in G6PD deficiency
• Avoided during
  pregnancy, G6PD deficient
Uses
• Primary use is radical cure of relapsing malaria
  15 mg daily for 14 days with dose of
  chloroquine
• Falciparum malaria 45 mg of single dose with
  chloroquine curative dose to kill gametes &
  cut down transmission of malaria.
• Tafenoquine:
  – More active slowly metabolized analog of
    primaquine, has advantage that it can be given on
    weekly basis.
• Bulaquine:
  – Congener of primaquine developed in india
  – Comparable antirelapse activity when used for 5
    days
  – Partly metabolized to primaquine
  – Better tolerated in G6PD deficiency
Mefloquine
• Quinoline methanol derivative developed to
  deal with chloroquine resistant malaria
• Rapidly acting erythrocytic schizonticide ,
  slower than chloroquine & quinine
• Effective against chloroquine sensitive &
  resistant plasmodia
• Mechanism of action similar to chloroquine
Pharmacokinetics
• Good but slow oral absorption
• High protein binding
• Concentrated in liver, lung, intestine
•  Extensive metabolism in liver, primarily
  secreted in bile , under goes enterohepatic
  circulation
• Long t1/2 = 2 – 3 weeks
Adverse events
• GIT:
    – bitter in taste, nausea, vomiting , abdominal pain ,
      diarrhoea
•       Neuropsychiatric disturbances:
    – anxiety, hallucinations, sleep disturbances, psychosis,
      errors in operating machinery, convulsions
• CVS:
    –    Bradycardia, sinus arhythmia, & QT prolongation
• Teratogenicity:
    – Avoided in first trimester
• Miscellaneous:
    – allergic skin reactions, hepatitis & blood dyscrasias
Uses
• Effective drug for MDR falciparum
 1. T/t of uncomplicated falciparum in MDR malaria
    should be used along with artesunate (ACT)
 2. Prophylaxis in MDR areas 250 mg per week
    started 2- 3 weeks before to asses side effects
• Due to fear of development of drug
  resistance mefloquine should not be used as
  drug for prophylaxis in residents of endemic
  area
Halofantrine
• Quinoline methanol
• Used in chloroquine resistant malaria since
  1980
• Erratic bioavailabilty, lethal cardiotoxicity &
  cross resistance to mefloquine limited its use
• Now a days used only when no other
  alternative available
• Adverse events; Nausea, vomiting, QT
  prolongation , diarrhoea, itching , rashes
• C/I: along with
  quinine, chloroquine, antidepressants, antips
Atovaquone
• Synthetic napthoquinone
• Rapidly acting erythrocytic schizonticide for
  plasmodium falciparum & other plasmodia
• MOA: Collapses mitochondrial membrane &
  interferes ATP production
• Proguanil potentiates action of atovaquone
  and prevents development of resistance
• Also used in P. Jivoreci & Toxoplasma gondii
  infections
Dihydrofolate reductase inhibitors
• Proguanil :
  – Biguanide converted to cycloguanil active
    compound
  – Act slowly on erythrocytic stage of vivax &
    falciparum
  – Prevents development of gametes
 Adverse effects:
   Stomatitis, mouth ulcers, larger doses depression
    of myocardium , megaloblastic anemia
 Not a drug for acute attack
 Causal prophylaxis: 100 – 200 mg daily
Pyrimethamine
• Diaminopyrimidine more potent than proguanil
  & effective against erythrocytic forms of all
  species.
• Tasteless so suitable for children
 Adverse events: megaloblastic
  anemia, thrombocytopenia, agranulocytosis.
Sulfadoxine-pyrimethamine
• Sequential blockade
• sulfadoxine 500 mg + pyrimethamine 25 mg, 3
  tablets once for acute attack
• Not recommended for prophylaxis
• Use:
  – single dose treatment of uncomplicated
    chloroquine resistant falciparum malaria
  – patients intolerant to chloroquine
  – First choice treatment for toxoplasmosis
Artemisinin
• Artemisinin is the active principle of the plant
  artimisia annua
• Sesquiterpine lactone derivative
• Most potent and rapid acting blood
  schizonticides
• Short duration of action
• high recrudescence rate
• Poorly soluble in water & oil
Artemisinin derivatives
• Artesunate
• Artemether
• Arteether
PLANT- ARTEMISIA ANNUA
Mechanism of action
• These compounds have presence of endoperoxide
  bridge
• Endoperoxide bridge interacts with heme in parasite
• Heme iron cleaves this endoperoxide bridge
• There is generation of highly reactive free radicals which
  damage parasite membrane by covalently binding to
  membrane proteins
Antimalarial action


              Artemisinin




               Conventional
               Treatment




                  Artemisinin
Artesunate
• Water soluble ester of dihydroartemisinin
• Dose: can be given oral, IM,IV, rectal
  – Oral
     • 100 mg BD on day 1
     • 50 mg BD day 2 to day 5
  – Parenteral
     • 120 mg on day 1 (2.4 mg/kg BD )
     • 60 mg OD ( 2.4 mg/kg) for 7 days
Artemether
• Methyl ether of dihydroartemisinin
• Dose:
  • Oral & IM
    • 80 mg BD on day 1 (3.2 mg/kg)
    • 80 mg OD (1.6 mg/kg) for 7 days
Arteether
• Ethyl ether of dihydroartemisinin
• Therapeutically equivalent to quinine in
 cerebral malaria
• A longer t1/2 & more lipophilic than
  artemether favouring accumulation in brain
• Dose:3.2 mg/kg on day1 followed by 1.6
  mg/kg daily for next 4 days
Adverse events
• Leucopenia
• Hypersensitivity: Drug fever, itching
• GIT: nausea, vomiting, abdominal pain
  (common)
• ECG changes: ST-T changes, QT prolongation
• Abnormal bleeding, dark urine
• Reticulocytopenia
Artemisinin based combination therapy
                (ACT)
• Artemisinin compunds are shorter acting drugs
• Monotherapy needs to be extended beyond
  disappearance of parasite to prevent
  recrudescence
• This can be prevented by combining 3-5 day
  regimen of artemisin compounds with one long
  acting drug like mefloquine 15 mg/kg single
  dose
• Indicated by WHO in acute uncomplicated
  resistant falciparum malaria
Why combination therapy
•   Rapid clinical & parasitological cure
•   High cure rates and low relapse rates
•   Absence of resistance
•   Good tolerability profile
ACT Regimens in use
• Artesunate – Sulfadoxine, pyrimethamine:
  – Adopted as first line in india under NMP
  – ARTESUNATE 100 mg BD for 3 days with S-P, 3
    tablets
• Artesunate Mefloquine:
  – By combining artesunate further spread of
    mefloquine resistance can be prevented
  – Artesunate 100 mg BD for 3 days, + mefloquine
    750 mg on second day & 500 mg on third day
Artemether & lumefantrine
• Lumefantrine is highly effective , long acting
  oral erythrocytic schizonticide related to
  mefloquine
• Highly lipophilic onset delayed , peak 6 hrs
• Available as fixed dose combination
• 80 mg artemether BD WITH 480 mg
  lumefantrine BD for 3 days
Other ACTs:
  – DHA – Piperaquine, Artesunate- pyronaridine
Tetracyclines
• Slow but potent action on erythrocytic stage
  of all MP & Pre-erythrocytic stage of
  falciparum
• Always used in combination with quinine or S-
  P for treatment of chloroquine resistant
  malaria
Management of Malaria
Prophylaxis of malaria
• Indication:
• Duration :1-2 weeks before to 4 weeks
  after returning from endemic area
• Drug regimens:
  – Chloroquine sensitive malaria: 300 mg / week
  – Chloroquine resistant malaria:
     • Mefloquine 250 mg once a week ,
     • Doxycycline 100 mg daily ,
     • Atovaquone + proguanil daily
Drugs not allowed for prophylaxis
• Quinine , artemisinin compounds
  – Shorter acting, higher toxicity
• Pyrimethamine sulfadoxine
• Amodiaquine
Acute attack of chloroquine sensitive
               malaria:
• Tab. Chloroquine phosphate 250 mg
  – Contains 150 mg of base
  – Give 4 tablets stat , 2 tablets after 8 hours and , 1
    tablet BD for 2 days
• Patients who cannot take orally
  – 3.5 mg/kg IM every 6 hrs for 3 days
• Tab primaquine 15 mg OD for 14 days in
  Plasmodium vivax, ovale
• Primaqine 45 mg single dose for falciparum
  after chloroquine (gametocidal)
Acute attack of chloroquine resistant
               malaria
A. Pts who can take orally:
 – 3 tablets of (Pyrimethamine + sulfadoxine) single
   dose followed by quinine 600 mg TDS for 2 days
   or
 – Tab Quinine 600 mg TDS X 3 days with Cap
   doxycycline 100 mg BD for 7 days or
 – Quinine 3 days with mefloquine or
 – (Atovaquone 250 mg + proguanil 100 mg) 4
   tab(Single dose ) for 3 days or
 – artesunate 100 mg BD x 3 days with Sulfadoxine-
   pyrimethamine or mefloquine
• Pts who cannot take orally
  – Inj Quinine Hcl 20 mg/kg in 500 ml dextrose saline
    over 4 hrs then
  – 10 mg/kg in dextrose saline over 2 hrs every 8 hrly
    till patient is able to swallow
  – Then quinine 600 mg TDS for 7 days &
    tetracycline/ doxycycline
                   Or
  – artemether / arteether injection
When should resistance be suspected
• All pts with complication
• Any pt who has already received chloroquine
  last 1 month
• Hb continues to fall in absence of bleeding &
  asexual forms persist along with symptoms
  after 48 hrs of treatment
Severe and complicated falciparum
                 malaria
•   Hyperparasitaemia
•   Hyperpyrexia
•   Fluid electrolyte disturbances, acidosis
•   Hypoglycemia
•   Cardiovascular collapse
•   Jaundice, severe anaemia
•   Spontaneous bleeding
•   Pulmonary edema
•   Renal failure
•   Hemoglobinuria, black water fever
•   Cerebral malaria
Treatment of severe and complicated
         falciparum malaria
• Artesunate 2.4 mg/kg IV/IM, BD on day1
  then 2.4 mg/kg daily for 7 days OR
• Artemether 3.2 mg/kg IM on day 1 then
  1.6 mg/kg daily for 7 days OR
• Arteether 3.2 mg/kg IM on day1, followed by
  1.6 mg/kg daily for next 4 days
  – Switchover to 3 Day oral ACT in between
    whenever patient can take oral medication
OR
• Quinine: 20 mg quinine salt/kg on admission
  (i.v. infusion in 5% dextrose/dextrose saline
  over a period of 4 hours) followed by
  maintenance dose of 10 mg/kg body weight 8
  hourly.
  – When ever patient can swallow orally switch over
    to oral quinine 10 mg/kg 8 hrly and complete 7
    days course
• Malaria in children:
  – Quinine parenteral high toxicity / oral well
    tolerated
  – Primaquine avoided in neonates
  – Mefloquine not used in children below 15 kg
    weight
• Acute malaria in pregnant women
  – Chloroqune in usual doses
  – Mefloquine C/I in first trimester
  – Primaquine/ tetracycline avoided
  – Anemia: folic acid & iron
Practice points
• Most antimalarials are bitter in taste give
  along with milk or fruit juice
• If vomiting occurs within hour of drug repeat
  full dose, in case of mefloquine repeat half
  dose
• If vomiting after 1 hour no need to repeat
• Postural hypotension : quinine, chloroquine
Drugs used in chloroquine resistant
                  malaria
•   Mefloquine
•   Quinine
•   Sulfadoxine pyrimethamine
•   Artemisinin compounds

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Antimalarial drugs

  • 2. Plasmodium species which infect humans Plasmodium vivax (tertian): Plasmodium ovale (tertian) Plasmodium falciparum (tertian) Plasmodium malariae (quartan) Plasmodium knowlesi:
  • 4.
  • 5. Life cycle of the malarial parasite True causal prophylactics Sporonticide Schizogony Sporogeny (asexual) (sexual) Causal prophylactics Supressives Man : Intermediate host Mosquito : Definitive host Gametocidal
  • 6. • Classification of antimalarial drugs – Therapeutic classification – Chemical classification
  • 7. Therapeutic classification • Causal prophylaxis: (Primary tissue schizonticides) – Destroy parasite in liver cells and prevent invasion of erythrocytes – Primaquine, proguanil • Supressives Prophylaxis: – Supress the erythrocytic phase and thus attack of malarial fever can be used as prophylactics – Chloroquine, proguanil, mefloquine, doxycycline
  • 8. Therapeutic classification • Clinical cure: erythrocytic schizonticides – used to terminate an episode of malarial fever • Fast acting high efficacy – Chloroquine, quinine, mefloquine, atovaquone, artemisinin • Slow acting low efficacy drugs – Proguanil, pyrimethamine, sulfonamides, tetracyclines
  • 9. Therapeutic classification • Radical curatives: – Eradicate all forms of P.vivax & P.ovale from the body – Supressive drugs + hypnozoitocidal drugs – For vivax: primaquine 15 mg daily for 14 days • Gametocidal: – Destroy gametocytes and prevent transmission – Primaquine, artemisinin – against all plasmodia – Chloroquine, quinine – Pl Vivax – Proguanil ,pyrimethamine – prevent development of sporozoites
  • 10. Chemical classification • 4 aminoquinolines: – Chloroquine, Hydroxychloroquine, Amodiaquine, Pyronari dine • 8 aminoquinolines: – Primaquine, Tafenoquine, Bulaquine • Cinchona alkaloids: – Quinine, Quinidine • Quinoline methanol: – Mefloquine • Biguanides – Proguanil, Chlorproguanil
  • 11. Chemical classification • Diaminopyrimidines – Pyrimethamine • Sulfonamides – Sulfadoxine, dapsone • Tetracyclines: – tetracycline, doxycycline • Naphthoquinone: – Atovaquone • Sesquiterpene lactones: – Artesunate, artemether, arteether
  • 12. • Chloroquine: – Synthesized by Germans in 1934 ( resochin) – d & l isomers, d isomer is less toxic – Cl at position 7 confers maximal antimalarial efficacy
  • 13. Mechanism of action Hemoglobin Globin utilized by malarial parasite Heme (highly toxic for malaria parasite) Chloroquine Quinine, (+) Heme Polymerase mefloquine (-) Hemozoin (Not toxic to plasmodium)
  • 14. Pharmacological actions 1. Antimalarial activity: – High against erythrocytic forms of vivax, ovale, malariae & sensitive strains of falciparum – Gametocytes of vivax – No activity against tissue schizonts – Resistance develops due to efflux mechanism 2. Other parasitic infections: – Giardiasis, taeniasis, extrainstestinal amoebiasis 3. Other actions: – Depressant action on myocardium, direct relaxant effect on vascular smooth muscles, antiinflammatory, antihistaminic , local
  • 15. Pharmacokinetics • Well absorbed, tmax 2-3 hrs , 60 % protein bound • Concentrated in liver , spleen, kidney, lungs , leucocytes • Selective accumulation in retina: occular toxicity • T1/2 = 3-10 days increases from few days to weeks
  • 16. Adverse drug reactions • Intolerance: – Nausea, vomiting, anorexia – skin rashes, angioneurotic edema, photosensitivity, pigmentation, exfoliative dermatititis – Long term therapy may cause bleaching of hair – Rarely thrombocytopenia, agranulocytosis, pancytopenia
  • 17. Adverse drug reactions • Occular toxicity: High dose prolonged therapy – Temporary loss of accommodation – Lenticular opacities, subcapsular cataract – Retinopathy: constriction of arteries, edema, blue black pigmentation , constricted field of vision. • CNS: – Insomnia, transient depression seizures, rarely neuromyopathy & ototoxicity • CVS: – ST & T wave abnormalities, abrupt fall in BP & cardiac arrest in children reported
  • 18. Dosage • 600 mg of base stat • 300 mg base after 8 hours • 150 mg of base BD for 2 days • 200 mg oral tablet of chloroquine phosphate consists of 150 mg base
  • 19. Chloroquine is administered in loading dose in malaria • Chloroquine is well absorbed after oral administration. It is extensively tissue bound and sequestrated by tissues particularly liver, spleen, kidney it has got large apparent volume of distribution • So it is given in loading dose to rapidly achieve the effective plasma conc.
  • 20. Therapeutic uses 1. Hepatic amoebiasis: 2. Giardiasis 3. Clonorchis sinensis 4. Rheumatoid arthritis 5. Discoid Lupus Erythematosus 6. Control manifestation of lepra reaction 7. Infectious mononucleosis
  • 21. • Hydroxy chloroquine: – Less toxic, properties &uses similar • Amodiaquine: – As effective as chloroquine – Pharmacological actions similar – Chloroquine resistant strains may be effective – Adverse events: GIT, headache , photosensitivity, rarely agranulocytosis – Not recommended for prophylaxis • Pyronaridine: effective in resistant cases
  • 22. Quinine • 1820 Pelletier & caventou isolated quinine from cinchona bark. • Mechanism of action: – Similar to chloroquine
  • 23. Pharmacological actions 1. Antimalarial action: – Erythrocytic forms of all malarial parasites including resistant falciparum strains . – Gametocidal for vivax & malariae 2. Local irritant effect: – Local pain sterile abcess. 3. Cardiovascular: – depresses myocardium, ↓ excitability, ↓ conductivity, ↑ refractory period, profound hypotension IV. 4. Miscellaneous actions: – Mild analgesic, antipyretic activity , stimulation of uterine smooth muscle, curaremimitic effect
  • 24. Adverse drug reactions Cinchonism: • Tinnitus, nausea & vomiting • Headache mental confusion, vertigo, difficulty in hearing & visual disturbances • Diarrhoea , flushing & marked perspiration • Still higher doses , exagerated symptoms with delirium , fever, tachypnoea, respiratory depression , cyanosis.
  • 25. Adverse drug reactions • Idiosyncrasy : similar to cinchonism but occurs in therapeutic doses • Cardiovascular toxicity: cardiac arrest, hypotension ,fatal arrhytmias • Black water fever: • Hypoglycemia:
  • 26. Uses • Malaria: – uncomplicated resistant falciparum malaria – Cerebral malarial • Myotonia congenita: 300 to 600 mg BD/ TDS • Nocturnal muscle cramps: 200 – 300 mg before sleeping • Spermicidal in vaginal creams • Varicose veins: along with urethane causes thrombosis & fibrosis of varicose vein mass
  • 27. • Primaquine: – Mechanism of action: Primaquine Converted to electrophiles Generates reactive oxygen species – Interferes with oxygen transport system
  • 28. Antimalarial action • Liver hypnozoites • Weak action against erythrocytic stage of vivax, so used with supressives in radical cure • No action against erythrocytic stage of falciparum • Has gametocidal action and is most effective antimalarial to prevent transmission disease against all 4 species
  • 29. Adverse effects • Gastrointestinal: – epigastric distress, abdominal cramps , • Hemopoetic: – mild anemia, methaemoglobinem ia, cyanosis, hemolytic anemia in G6PD deficiency • Avoided during pregnancy, G6PD deficient
  • 30. Uses • Primary use is radical cure of relapsing malaria 15 mg daily for 14 days with dose of chloroquine • Falciparum malaria 45 mg of single dose with chloroquine curative dose to kill gametes & cut down transmission of malaria.
  • 31. • Tafenoquine: – More active slowly metabolized analog of primaquine, has advantage that it can be given on weekly basis. • Bulaquine: – Congener of primaquine developed in india – Comparable antirelapse activity when used for 5 days – Partly metabolized to primaquine – Better tolerated in G6PD deficiency
  • 32. Mefloquine • Quinoline methanol derivative developed to deal with chloroquine resistant malaria • Rapidly acting erythrocytic schizonticide , slower than chloroquine & quinine • Effective against chloroquine sensitive & resistant plasmodia • Mechanism of action similar to chloroquine
  • 33. Pharmacokinetics • Good but slow oral absorption • High protein binding • Concentrated in liver, lung, intestine • Extensive metabolism in liver, primarily secreted in bile , under goes enterohepatic circulation • Long t1/2 = 2 – 3 weeks
  • 34. Adverse events • GIT: – bitter in taste, nausea, vomiting , abdominal pain , diarrhoea • Neuropsychiatric disturbances: – anxiety, hallucinations, sleep disturbances, psychosis, errors in operating machinery, convulsions • CVS: – Bradycardia, sinus arhythmia, & QT prolongation • Teratogenicity: – Avoided in first trimester • Miscellaneous: – allergic skin reactions, hepatitis & blood dyscrasias
  • 35. Uses • Effective drug for MDR falciparum 1. T/t of uncomplicated falciparum in MDR malaria should be used along with artesunate (ACT) 2. Prophylaxis in MDR areas 250 mg per week started 2- 3 weeks before to asses side effects • Due to fear of development of drug resistance mefloquine should not be used as drug for prophylaxis in residents of endemic area
  • 36. Halofantrine • Quinoline methanol • Used in chloroquine resistant malaria since 1980 • Erratic bioavailabilty, lethal cardiotoxicity & cross resistance to mefloquine limited its use • Now a days used only when no other alternative available • Adverse events; Nausea, vomiting, QT prolongation , diarrhoea, itching , rashes • C/I: along with quinine, chloroquine, antidepressants, antips
  • 37. Atovaquone • Synthetic napthoquinone • Rapidly acting erythrocytic schizonticide for plasmodium falciparum & other plasmodia • MOA: Collapses mitochondrial membrane & interferes ATP production • Proguanil potentiates action of atovaquone and prevents development of resistance • Also used in P. Jivoreci & Toxoplasma gondii infections
  • 38. Dihydrofolate reductase inhibitors • Proguanil : – Biguanide converted to cycloguanil active compound – Act slowly on erythrocytic stage of vivax & falciparum – Prevents development of gametes  Adverse effects:  Stomatitis, mouth ulcers, larger doses depression of myocardium , megaloblastic anemia  Not a drug for acute attack  Causal prophylaxis: 100 – 200 mg daily
  • 39. Pyrimethamine • Diaminopyrimidine more potent than proguanil & effective against erythrocytic forms of all species. • Tasteless so suitable for children  Adverse events: megaloblastic anemia, thrombocytopenia, agranulocytosis.
  • 40. Sulfadoxine-pyrimethamine • Sequential blockade • sulfadoxine 500 mg + pyrimethamine 25 mg, 3 tablets once for acute attack • Not recommended for prophylaxis • Use: – single dose treatment of uncomplicated chloroquine resistant falciparum malaria – patients intolerant to chloroquine – First choice treatment for toxoplasmosis
  • 41. Artemisinin • Artemisinin is the active principle of the plant artimisia annua • Sesquiterpine lactone derivative • Most potent and rapid acting blood schizonticides • Short duration of action • high recrudescence rate • Poorly soluble in water & oil
  • 42. Artemisinin derivatives • Artesunate • Artemether • Arteether
  • 44. Mechanism of action • These compounds have presence of endoperoxide bridge • Endoperoxide bridge interacts with heme in parasite • Heme iron cleaves this endoperoxide bridge • There is generation of highly reactive free radicals which damage parasite membrane by covalently binding to membrane proteins
  • 45. Antimalarial action Artemisinin Conventional Treatment Artemisinin
  • 46. Artesunate • Water soluble ester of dihydroartemisinin • Dose: can be given oral, IM,IV, rectal – Oral • 100 mg BD on day 1 • 50 mg BD day 2 to day 5 – Parenteral • 120 mg on day 1 (2.4 mg/kg BD ) • 60 mg OD ( 2.4 mg/kg) for 7 days
  • 47. Artemether • Methyl ether of dihydroartemisinin • Dose: • Oral & IM • 80 mg BD on day 1 (3.2 mg/kg) • 80 mg OD (1.6 mg/kg) for 7 days
  • 48. Arteether • Ethyl ether of dihydroartemisinin • Therapeutically equivalent to quinine in cerebral malaria • A longer t1/2 & more lipophilic than artemether favouring accumulation in brain • Dose:3.2 mg/kg on day1 followed by 1.6 mg/kg daily for next 4 days
  • 49. Adverse events • Leucopenia • Hypersensitivity: Drug fever, itching • GIT: nausea, vomiting, abdominal pain (common) • ECG changes: ST-T changes, QT prolongation • Abnormal bleeding, dark urine • Reticulocytopenia
  • 50. Artemisinin based combination therapy (ACT) • Artemisinin compunds are shorter acting drugs • Monotherapy needs to be extended beyond disappearance of parasite to prevent recrudescence • This can be prevented by combining 3-5 day regimen of artemisin compounds with one long acting drug like mefloquine 15 mg/kg single dose • Indicated by WHO in acute uncomplicated resistant falciparum malaria
  • 51. Why combination therapy • Rapid clinical & parasitological cure • High cure rates and low relapse rates • Absence of resistance • Good tolerability profile
  • 52. ACT Regimens in use • Artesunate – Sulfadoxine, pyrimethamine: – Adopted as first line in india under NMP – ARTESUNATE 100 mg BD for 3 days with S-P, 3 tablets • Artesunate Mefloquine: – By combining artesunate further spread of mefloquine resistance can be prevented – Artesunate 100 mg BD for 3 days, + mefloquine 750 mg on second day & 500 mg on third day
  • 53. Artemether & lumefantrine • Lumefantrine is highly effective , long acting oral erythrocytic schizonticide related to mefloquine • Highly lipophilic onset delayed , peak 6 hrs • Available as fixed dose combination • 80 mg artemether BD WITH 480 mg lumefantrine BD for 3 days Other ACTs: – DHA – Piperaquine, Artesunate- pyronaridine
  • 54. Tetracyclines • Slow but potent action on erythrocytic stage of all MP & Pre-erythrocytic stage of falciparum • Always used in combination with quinine or S- P for treatment of chloroquine resistant malaria
  • 56. Prophylaxis of malaria • Indication: • Duration :1-2 weeks before to 4 weeks after returning from endemic area • Drug regimens: – Chloroquine sensitive malaria: 300 mg / week – Chloroquine resistant malaria: • Mefloquine 250 mg once a week , • Doxycycline 100 mg daily , • Atovaquone + proguanil daily
  • 57. Drugs not allowed for prophylaxis • Quinine , artemisinin compounds – Shorter acting, higher toxicity • Pyrimethamine sulfadoxine • Amodiaquine
  • 58. Acute attack of chloroquine sensitive malaria: • Tab. Chloroquine phosphate 250 mg – Contains 150 mg of base – Give 4 tablets stat , 2 tablets after 8 hours and , 1 tablet BD for 2 days • Patients who cannot take orally – 3.5 mg/kg IM every 6 hrs for 3 days • Tab primaquine 15 mg OD for 14 days in Plasmodium vivax, ovale • Primaqine 45 mg single dose for falciparum after chloroquine (gametocidal)
  • 59. Acute attack of chloroquine resistant malaria A. Pts who can take orally: – 3 tablets of (Pyrimethamine + sulfadoxine) single dose followed by quinine 600 mg TDS for 2 days or – Tab Quinine 600 mg TDS X 3 days with Cap doxycycline 100 mg BD for 7 days or – Quinine 3 days with mefloquine or – (Atovaquone 250 mg + proguanil 100 mg) 4 tab(Single dose ) for 3 days or – artesunate 100 mg BD x 3 days with Sulfadoxine- pyrimethamine or mefloquine
  • 60. • Pts who cannot take orally – Inj Quinine Hcl 20 mg/kg in 500 ml dextrose saline over 4 hrs then – 10 mg/kg in dextrose saline over 2 hrs every 8 hrly till patient is able to swallow – Then quinine 600 mg TDS for 7 days & tetracycline/ doxycycline Or – artemether / arteether injection
  • 61. When should resistance be suspected • All pts with complication • Any pt who has already received chloroquine last 1 month • Hb continues to fall in absence of bleeding & asexual forms persist along with symptoms after 48 hrs of treatment
  • 62. Severe and complicated falciparum malaria • Hyperparasitaemia • Hyperpyrexia • Fluid electrolyte disturbances, acidosis • Hypoglycemia • Cardiovascular collapse • Jaundice, severe anaemia • Spontaneous bleeding • Pulmonary edema • Renal failure • Hemoglobinuria, black water fever • Cerebral malaria
  • 63. Treatment of severe and complicated falciparum malaria • Artesunate 2.4 mg/kg IV/IM, BD on day1 then 2.4 mg/kg daily for 7 days OR • Artemether 3.2 mg/kg IM on day 1 then 1.6 mg/kg daily for 7 days OR • Arteether 3.2 mg/kg IM on day1, followed by 1.6 mg/kg daily for next 4 days – Switchover to 3 Day oral ACT in between whenever patient can take oral medication
  • 64. OR • Quinine: 20 mg quinine salt/kg on admission (i.v. infusion in 5% dextrose/dextrose saline over a period of 4 hours) followed by maintenance dose of 10 mg/kg body weight 8 hourly. – When ever patient can swallow orally switch over to oral quinine 10 mg/kg 8 hrly and complete 7 days course
  • 65. • Malaria in children: – Quinine parenteral high toxicity / oral well tolerated – Primaquine avoided in neonates – Mefloquine not used in children below 15 kg weight • Acute malaria in pregnant women – Chloroqune in usual doses – Mefloquine C/I in first trimester – Primaquine/ tetracycline avoided – Anemia: folic acid & iron
  • 66. Practice points • Most antimalarials are bitter in taste give along with milk or fruit juice • If vomiting occurs within hour of drug repeat full dose, in case of mefloquine repeat half dose • If vomiting after 1 hour no need to repeat • Postural hypotension : quinine, chloroquine
  • 67. Drugs used in chloroquine resistant malaria • Mefloquine • Quinine • Sulfadoxine pyrimethamine • Artemisinin compounds

Editor's Notes

  1. Malaria is one of the most devastating parasitic infections all over the world all over the world 1-3 million deaths occur world wide and in india about 8 lac deaths per year due to malaria
  2. Transmission of malaria is by female anopheles mosquito
  3.  Nobel Prize for Physiology or Medicine in 1902 for his work on malaria. His discovery of the malarial parasite in the gastrointestinal tract of the Anopheles mosquito led to the realization that malaria was transmitted by Anopheles, and laid the foundation for combating the disease.Charles Laveran first visualised the malaria parasite in blood in 1880,
  4. Proguanil is a causal prophylactic for falciparum malaria but is not employed routinely. Because it has to be given daily and is not very effective against p.VivaxPrimaquine is causal prophylactic for all species of malaria. But has not been used in mass programmes due to toxic potential. 0.5 mg/kg daily in NoN G6PD deficient
  5. Fast acting drugs can be used singly to treat attacks of malarial fever: faster acting drugs are preferred in falciparum malaria where delay in treatment may result in death even if the parasites are cleared from blood. The exoerythrocytic phase of vivax and ovale persists which can cause relapses without subsequent re-infection in vivax and ovaleRecrudescence can occur in falciparum malaria if blood is not totally cleared of parasite by drug Slow efficacy drugs are used only in combination for clinical cure
  6. Drugs which attack the exoerythrocytic stage (Hypnozoites ) given together with a clinical curative achieve total eradication of parasite from the patients bodyRadical curative is needed in relapsing malaria. While in falciparum malaria – adequate treatment of clinical attack leaves no parasite in the body Indiacted in areas with low level of transmission , patients treated during an epidemic along with effective vector control measures to cut down transmissionAdequate control of Clinical attacks will reduce formation of gametes: a single 45 mg dose of primaquine is employed after clinical cure of falciparum malaria to kill gametes to cut down transmission to mosquito – not necessary when artemisinin is used for clinical cure.
  7. Mannich base: pyronaridineAmino alcohols: halofantrine, lumefantrine
  8. Synthesized as a part of extensive cooperative programme of antimalarial research in US during world war2 . Proved most promising and was released for field trials .It was discovered that the compound had been synthesized by germans as early as 1934 under name of resochin at bayer laboratories in germany but had been rejected due to toxicity in avian modelsChlorine atom attached to position 7 of quinoline ring confers most potent antimalarial activity. Short chain derivative and piperaquine new compunds SAR : demonstrate activity against chloroquine resistant malariaHydroxychloroquine: N-ethyl substituent of chloroquine is hydroxylated same as chlorpquine. But preferred over chloroquine in treatment of rheumatoid arthritis and lupus erythematosus because in the high doses required it may cause less ocular toxicity.
  9. Oxidative damage to the membranes , digestive proteases & other critical biomolecules of malarial parasite Heme polymerase present inside lysosomes of the malarial parasite which convert toxic heme to non toxic hemozoinNow chloroquine concentrates in the acidic lysosomes binds to liberated heme to form hemequinoline complex which interupts the hemepolymerisation by inhibiting enzyme heme polymerase Chloroquine also inhibits RNA & DNA synthesis at higher conc but these effects are unlikely to be involved in MOA MECHANISM OF QUININE & MEFLOQUINE ARE SIMILAR
  10. Partly metabolized by liver and slowly excreted in urine. The early plasma half life varies from 3-10 days, because of tighttissue binding small amounts persist in body with terminal half life of 1-2 months
  11. Depresses variety of enzymatic processes, reduces ciliary activity , inhibits phagacytosis & growth of protoplasm so called general protoplasmic poison.
  12. A large single dose or higher therapeutic
  13. Triad of hemolysis, hemoglobinemia, hemoglobinuria with feverRare type of hypersensitivity to quinine therapy having immunological basis. Presence of incompletely supressed falciparum malaria.
  14. Myotoniacongenita: heriditorymyopathy characterized by tonic spasm of skeletal
  15. India 5 day therapy
  16. Mefloquine resistance among plasmodium falciparum has become common in Thailand cambodia and myanmar, as it has not been used extensively in indiamefloquine resistance is not a problem over here. But due to its long half life chances of selection of resistant strains are high; mefloquine resistant isolates have been reported from gujrat and andhrapradesh. Resistance to mefloquine confers resistance to quinine and halofantrine
  17. Disturbed sense of balance, ataxia, neuropsychiatric reactions are dose related and subside in 1-3 weeks
  18. Because of its toxicity cost and long half life use restricted to areas where such strains are prevalent . TO check spread of resistance should be used with artesunate. For vivax malaria should be used only when chloroquine and quinine + doxycycline resistant. It cannot be given parenterally and is not used in complicated cerebral malaria
  19. Fixed dose combination of atovaquone available with proguanilatovaquone 250 mg + proguanil 100 mg 4 tablets daily single dose for 3 days in resistant malaria
  20. Slow acting erythrocyticschizonticide which also inhibits the preerythrocytic stage of p.falciparum. Resistance develops rapidly due to mutationsal changes in plasmodialDHFRase enzyme
  21. High affinity for plasmodial enzyme 200o times greater than for mammalian enzyme.
  22. Compliance is good
  23. Artimisiaannua is used in chinese traditional medicine as quinghauso as Elicit quicker defervescence and clearing of parasitemia in 48 hours Artemisinin is poorly soluble in water and oil several derivatives have been produced of which 3 are marketed in India Do not kill hypnozoites but have some action on gametocytes of falciparum Adults and children: 25mg/Kg on the first day followed by 12.5mg/Kg on the second and third day in combination with mefloquine (15mg/Kg) in a single dose on the second day. In some areas, a higher dose (25mg/Kg) of mefloquine may be required for a cure to be obtained.
  24. Dihydroartemisinin
  25. Artemisinin is not very soluble either in water or oil. This and its short elimination half life led to the search for the derivatives that had improved pharmacological properties as well as better antimalarial activityConverted to dihydroartemisinin, which is a potent antimalarial compound Available for oral and rectal use in several countries in Asia, especially in Vietnam
  26. Intraparasitic ferrous protoporphyrinIV catalyses breakdown of endoperoxide bridge Chloroquine antagonizes the antimalarial activityIron chelators antagonize antiparasitic effect of artemisinin
  27. These compunds are mainly schizonticides and are effective against plasmodium vivax as well as chloroquine resistant and sensitive strains of plasmodium falciparum, they are useful in cerebral malaria and MDR MALARIA
  28. Trade name : falcigoOral: artesunate & artemether , IM: ALL 3, IV & rectal artesunateDuration of action 3 to 4 hrs
  29. Trade nameRmether capsule & injDuration of action: 4 to 11 hours
  30. ARTEMETHER & ARTESUNATE ARE PRODRUGS CONVERTED TO DIHYDROARTEMISININ RESPONSIBLE FOR ACTIVITY
  31. No serious adverse events
  32. Artemisinin compounds rapidly kill more than > 95 % of the plasmodia and only leave small biomass of the parasites to be killed by long t1/2 drugs
  33. Adverse events: headache, dizziness, sleep disturbances, abdominal pain, arthralgia, pruritis & rash
  34. Other measures Causal prophylaxis Supressive prophylaxis
  35. After returning home a traveller who has been heavily exposed to malaria and not G6PD deficient should be treated with primaquine 15 mg base daily for 14 days in order to eliminate hepatic forms of plasmodium vivax and ovale : causal prophylaxis Other measures for prophylaxis of malaria
  36. Complications: severe anemia, jaundice, renal failure
  37. One or more of above features
  38. Supportive measures:ICU administration Good nursing care, Tepid sponging, sodium bicarbonateHypoglycemia, anemia, BP , Increase ICT GC, urea, mannitol not used now a days
  39. ; infusion rate should not exceed 5 mg/kgbody weight per hour. If parenteral quinine therapy needs to be continued beyond 48 hours, dose should be reduced to 7 mg/kg body weight 8 hourly.If possible oral quinine should be replaced by 3 daY ACT TREATMENT