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
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.
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
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
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
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
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
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
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
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
Notas del editor
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
Transmission of malaria is by female anopheles mosquito
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,
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
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
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.
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.
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
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
Depresses variety of enzymatic processes, reduces ciliary activity , inhibits phagacytosis & growth of protoplasm so called general protoplasmic poison.
A large single dose or higher therapeutic
Triad of hemolysis, hemoglobinemia, hemoglobinuria with feverRare type of hypersensitivity to quinine therapy having immunological basis. Presence of incompletely supressed falciparum malaria.
Myotoniacongenita: heriditorymyopathy characterized by tonic spasm of skeletal
India 5 day therapy
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
Disturbed sense of balance, ataxia, neuropsychiatric reactions are dose related and subside in 1-3 weeks
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
Fixed dose combination of atovaquone available with proguanilatovaquone 250 mg + proguanil 100 mg 4 tablets daily single dose for 3 days in resistant malaria
Slow acting erythrocyticschizonticide which also inhibits the preerythrocytic stage of p.falciparum. Resistance develops rapidly due to mutationsal changes in plasmodialDHFRase enzyme
High affinity for plasmodial enzyme 200o times greater than for mammalian enzyme.
Compliance is good
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.
Dihydroartemisinin
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
Intraparasitic ferrous protoporphyrinIV catalyses breakdown of endoperoxide bridge Chloroquine antagonizes the antimalarial activityIron chelators antagonize antiparasitic effect of artemisinin
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
Trade name : falcigoOral: artesunate & artemether , IM: ALL 3, IV & rectal artesunateDuration of action 3 to 4 hrs
Trade nameRmether capsule & injDuration of action: 4 to 11 hours
ARTEMETHER & ARTESUNATE ARE PRODRUGS CONVERTED TO DIHYDROARTEMISININ RESPONSIBLE FOR ACTIVITY
No serious adverse events
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
Other measures Causal prophylaxis Supressive prophylaxis
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
Complications: severe anemia, jaundice, renal failure
One or more of above features
Supportive measures:ICU administration Good nursing care, Tepid sponging, sodium bicarbonateHypoglycemia, anemia, BP , Increase ICT GC, urea, mannitol not used now a days
; 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