revised programs on malaria and management of malaria

1. 1
Vishnupriya M.D NMCH

2.  The oldest diseases known to mankind that has profound impact
on our history.
 Malaria is a vector-borne infectious disease caused by single-celled
protozoan parasites of the genus Plasmodium.
 Malaria is transmitted from person to person by the bite of
female mosquitoes.
2

3. INDIA:
NMEP started in 1958 caused malaria complete disappearance but
came back in 1970 and still now prevails a major disease
changed to NAMP then finally named it to NVBDCP
WHO :
2012 estimated 627 000 deaths (with an range of 473 000 to
789 000), mostly among African children.
Mortality rates ↓ 45% globally since 2000, by 49% in the African
Region.
3

4. Plasmodium falciparum : Falciparum malaria or Malignant Tertian
malaria
Plasmodium vivax : Benign Tertian, Tertian Malaria
Plasmodium malariae: Quartan malaria
Plasmodium ovale: Ovale tertian Malaria
Plasmodium knowlesi a species that causes malaria among
monkeys.
4

5.  Transfusion of infected blood, congenitally, and by sharing
needles, but mainly by the bites of female Anopheles mosquitoes
 Man develops disease after 10 to 14 days of being bitten by an
infective mosquito
Life cycle of malarian parasite:
1) Hepatic cycle/pre or exo Erythrocytic cycle
2) Erythrocytic cycle
3)Sexual forms
5

6. 6

7. P. falciparum: Most dangerous invading
erythrocytes of any age, producing
endotoxin-like products, cause heavy
parasitemia, hypoglycemia, and shock with
multiorgan failure.
Delay in treatment may lead to death. If
treated early, the infection usually
responds within 48 hours.
7

8.  P. vivax has low mortality rate - untreated adults relapses caused
by the reactivation of latent tissue forms.
 (3) P. ovale affects periodicity and relapses similar to those of P.
vivax, but it is milder.
 (4) P. malariae causes a generally indolent infection that is
common in localized areas of the tropics. Clinical attacks may
occur years or decades after infection.
8

9.  Clinical Diagnosis
 Malaria Blood Smear
 Fluorescent microscopy
 Antigen Detection
 Serology
 Polymerase Chain Reaction
9

10.  Coma / cerebral malaria, convulsions
 Renal Impairment
 Noncardiogenic pulmonary edema
 Liver Dysfunction
 Hypoglycemia
10

11.  Metabolic acidosis/acidemia
 Hematological abnormality like hemoglobinuria,
 Normocytic anemia, bleeding, DIC
 Other complications : jaundice, extreme weakness,
hyperparasitemia, impaired consciousness
 Hypotension/shock
11

12.  1.prevent & treat clinical attack of malaria (prophylactic)
 2.completely eradicate the parasite from pt’s body (clinical
cure)
 3.reduce the human reservoir of infection – cut down
transmission to mosquito (gametocidal)
12

13. 13

14. 4- Aminoquinolines – Chloroquine, Amodiaquine, Piperaquine
Quinoline- methanol – Mefloquine
Chinchona alkaloid - Quinine, Quinidine
Biguanide - Proguanil
Diaminopyrimidine- Pyrimethamine
8-Aminoquinoline – Primaquine,Tafenoquine
14

15. Sulfonamides & sulfone- Sulfadoxine, Sulfamethopyrazine,
Dapsone
Antibiotics- Tetracycline,Doxycycline,Clindamycine
Sesquiterpine - Artesunate
Lactones- Artemether, Arteether,Arterolane
Amino alcohols - Halofantrine,Lumefantrine
Napthyridine - Pyronaridine
Napthoquinone - Atovaquone
15
Classification cont..

16.  Discovered in 1934 by Hans Andersag and coworker
 Produced in U.S , introduced into clinical practice in 1947 for the
prophylactic treatment of malaria
Spectrum of activity
• Rapid acting Erythrocytic schizonticide against all species of
malaria
 MOA :
• Accumulates in acidic vacuole of parasite it increases ph & inhibits
heme polymerisation.
• By formation CQ -heme complex it damages plasmodial membrane
complex inhibits formation of hemozoin
16

17. Resistance to chloroquine
PFCRT gene seen in chloroquine resistant p.falciparum it pumps out
the drug protecting heme
 ↓ ability of parasite to accumulate drug is the cause
NVBDCP : first line treatment against P.vivax & it slowly
developing resistance too within 1-2wks of treatment
 P.vivax resistance to Chloroquine : Quinine with
Doxycycline/Clindamycin or ACT followed by Primaquine for
radical cure is treatment of choice
17

18. Absorbed orally, rapid absorption from IM, SC.
•Concentrated in various tissues like liver, spleen, kidney, lungs &
melanin.
•Distribution in brain & spinal cord with large apparent volume of
distribution -13000 liters in adult,
• loading dose – to attain therapeutic concentration in plasma & steady
state concentration
•t1/2 : 214 h, 60% plasma protein bound
•Metabolism- two active forms
18

19. • Desethylchloroquine & Bisdesethyl chloroquine by CYP-450 in
liver
• 50% eliminated by systemic and remaining eliminated renally
• On parentral administration entry is rapid & removal is slow
causes toxicity
• To prevent it slow IV & S.C/I.M is given in small divided doses
19

20. Therapeutic uses OF Chloroquine
1.Malaria prophylaxis :
300mg once a week for prevention
person visiting endemic area should receive one week before and four
week after
DDoossee ooff CChhlloorrooqquuiinnee
Uncomplicated vivax /ovale/ malaria:
600mg(10mg/kg)- 300mg(5mg/kg) after 8hrs,continue for next 2
days total 25mg/kg over 3 days + primaquine
15mg(0.25mg/kg)daily for 14 days
Chloroquine sensitive falciparum
Dose as above + primaquine 45mg(0.75mg/kg) single
dose(gametocidal)
20

21. Other uses of Chloroquine:
Extra intestinal amoebiasis/hepatic amaoebiasis :
500mg TDS for 2 Days/ 200mg BD for 2-3 wks
Giardiasis: Metronidazole is preferred
Clonorchis sinensis :250mg daily for 6wks
Rheumatoid arthritis:250mg 6-12 mths once a week
Lepra reaction –TYPE 2
SLE :250-500mg daily 1-4wks followed by maintenance
21

22. Common:
Nausea, vomiting, anorexia, itching, epigastric pain, difficult in
accommodation, headache are frequent & unpleasant
Toxic effects after prolonged use :
•Skin eruptions, headache, blurring of vision, diplopia, confusion &
convulsions.
•EKG changes : abnormal T waves, Wide QRS interval reversible
•Discoloration of nail beds, hairs & mucous membrane
•Haemolysis & blood dyscrasis
22

23. Adverse effects of chloroquine cont…
Retinopathy with reduced visual acuity - accumulation of drug in
melanin rich tissues (Bulls eye maculopathy) –reversible
Ototoxicity irreversible
Myopathy, cardiomyopathy, peripheral neuropathy, suicidal
tendency occurs
Periodic neurological and retinal check up should be done
23

24. >5g
Cardiovascular – hypotension due to vasodilatation, suppressed
myocardiac function, cardiac arrhythmias & cardiac arrest
CNS – mental confusion, convulsion & coma
24

25.  with Mefloquine convulsion will occur
 Digoxin level increases used along
 With gold & phenylbutazone dermatitis will occur
 Drug should be avoided in patients with ocular ,hepatic disease
,hemorrhage, hematological disease, peptic ulcer & neurological
disease
25

26.  Epilepsy attacks will be precipitated in epileptic patients
 Myasthenia gravis will worsen
 Haemolysis occurs in G6PD deficient patients
 Aggrevates exfoliative dermatitis & psoriasis
26

27.  ↓ cost & safety in chloroquine resistance P.falciparum in certain
areas
 Faster action & better tolerance than chloroquine
 Prophylactically not used because of hepatotoxicity &
agranulocytosis in certain areas can be used in clinical attacks
Dosage :
25-35mg/kg for 3 days (10mg/kg is given immediately following
5mg/kg after 6hrs then 5mg/kg for next 2 days)
Mechanism, resistance, uses & ADR are similar to chloroquine
27

28.  Chloroquine Congener with similar mechanism
 High efficacy, erythrocytic schizonticide with prolonged action
& onset is slow
Activity:
Chloroquine sensitive & Chloroquine resistant P. falciparum
malaria
28

29. Mefloquine :
Tested during world war II, introduced in 1963
Its 4-quinoline methanol related chemically to quinine used in
chloroquine resistant P.falciparum malaria
Faster acting erythrocytic schizonticide slower than Chloroquine or
quinine.
Effective against Chloroquine sensitive organism also
Its suppressive prophylactic for multi resistant falciparum & other
types of malariae
29

30. Relapses - vivax , due to long t1/2 chances of resistant strains are
high
Cross resistance is seen with Quinine & Halofantrine
MOA of Mefloquine :
 Similar to morphological changes in the intraerythrocytic
parasite of Chloroquine & Quinine
 Act in cytosol of the parasite
 Mechanism is unclear it can also inhibit heme polymerization
forming toxic complex with heme & damages membrane
30

31. Enhanced translation of Pfmdr1 gene
Pharmacokinetics of Mefloquine :
Well absorbed orally, enhanced in presence of food
High plasma protein bound 98% & concentrated in many organs
Metabolism in liver, 10 secreted in bile, undergoes enterohepatic
circulation, t1/2: 2-3wks
31

32.  1.Prophylaxis :
Reserved for prevalent Chloroquine resistant P.falciparum areas
Dose: 5mg/kg or 250mg/wk for adults 1-2wks before travel.
 2.Treatment of malaria :
Reserve drug for multi drug resistance mainly Chloroquine resistant
vivax or falciparum
3.Current recommendation :
With Artesunate as ACT For uncomplicated falciparum malaria
32

33. 25mg/kg - 1.25gm single or 2 doses of 750 & 500mg 12hr apart
Children weight < 45kg :
First dose 15mg/kg → 10mg/kg after 12h after meals with plenty of
water since its irritant
Adverse drug reactions :
Common :
Dizziness, nausea, vomiting, diarrhoea ,abdominal pain, sinus
bradycardia & QT prolongation
33

34. Dose related effects :
 Neuropsychiatric reactions present
 Rare-hematological , hepatic & cutaneous toxicity
 Safe during pregnancy but should be avoided in first trimester
Drug Interactions :
Halofantrine or Quinidine/Quinine or Chloroquine with this drug
causes QT lengthening & cardiac arrest reported.
Avoided : Epileptic patients, Neuropsychiatric disorders
34

35. Quinine
Isolated from bark of chinchona tree in 1820,due to military
importance many drugs were developed
Its levorotatory alkaloid
Spectrum Activity of Quinine :
Erythrocytic schizonticide for all species
Concentrated in food vacuole , less effective more toxic than
Chloroquine
Kills vivax & malariae gametes & also effective against
Chloroquine resistant & falciparum resistant strains

35

36.  Terminates acute attack but does not completely eliminate the
parasite totally Doxycycline or Clindamycin are used
 Its local irritant , anesthetic ,weak analgesic & antipyretic
MOA of Quinine
 It forms heme – quinine complex ,
 Inhibits polymerization of heme to hemozoin
 Damages parasite membrane & kills it
Resistance:
 Similar to Mefloquine
 Have emerged in some parts of India
36

37.  Rapidly absorbed orally, peaks -5hr
 70% bound to alpha1 acid glycoprotein ↑ during malarial infection
 Metabolized in liver by CYP3A4
 Excreted in urine, crosses placental barrier
t1/2 9-18 hr, vol of distribution 100 L in adults
37

38. Uses of Quinine
1. Uncomplicated Chloroquine resistant malaria :
Its used orally alternative to S/P-ACT
NVBDCP : 7 day quinine 600mg 8hrly+ Doxycycline 100mg
daily/clindamycin 600mg 12hrly is second line treatment in
chloroquine resistance to falciparum & vivax malaria
38

39.  Uses of quinine cont…
Complicated & severe malaria-cerebral malaria:
Dose : (7 days course)
Loading dose : 20mg/kg i.v over 4hrs diluted in 5% dextrose to
prevent hypoglycemia
Maintenance Dose: 10mg/kg over 4hr in adults or 2hr in children
every 8hr
 Then switch over to oral 10mg/kg 8hrly
39

40.  Parental Artemisinin are fast ,more effective, better tolerated and
now preferred over Quinine for severe malaria
 2. Nocturnal muscle cramps & myotonia congenita –
Single tablet 300mg bed time
Adverse effects of Quinine
 Higher doses : Affects hearing & vision Cardio depressant , anti
arrhythmic & hypotensive actions similar to Quinidine
 On rapid i.v it causes hypoglycemia
40

41.  Toxicity : 8-10g taken in single dose may be fatal
Cinchonism :reversible
 Ringing in ears, nausea, vomiting, headache, mental confusion,
vertigo, difficulty in hearing & visual disturbance, diarrhoea
,flushing & marked perspiration
Poisoning higher doses:
 QT prolongation during i.v
 some develop idiosyncratic/hypersensitive reactions
41

42. Occasionally:
Haemolysis in pregnant women – falciparum malaria causing
hemoglobin urea & kidney damage
Caution : pregnant women only life threatening infection it
can be used
42

43. Slow acting erythrocytic schizontocide
Inhibits preerythrocytic stage of P.fal. gametocytes prevents
its development
It gets converted to active form cycloguanil, which inhibits
plasmodial DHFRase
MOA :
Inhibits DHFRase-thymidylate synthetase
43

44. partial cross resistance with pyrimethamine,
resistance develops due to mutation of DHFRase –thymidylate
Pharmacokinetics
 Slow absorption
 Except erythrocytes no accumulation in tissue
 Peak plasma concentration : 5hr, t1/2:16-20h,
 Noncumulative, well tolerated
 Racial variations seen
 Excreted : urine
44

45. Prophylaxis : ( P.falciparum & vivax )
Dose:
> 200mg daily in adults & children 4weeks after leaving endemic
area
Currently its either prophylaxis nor for clinical attack
Causal prophylaxis:
400mg proguanil + Atovaquine 1g for 3 days in multidrug
resistance
suppressive prophylactic :
With chloroquine in moderately CQ resistant P.falciparum areas.
45

46.  Mild abdominal symptoms,
 Occasional stomatitis, haematuria, rashes & transient loss of hair
Pyrimethamine
 It direct inhibitor of DHFRase
 Its slow acting blood schizonticide & More potent than Proguanil
 Used with Sulfonamide or Dapsone to prevent resistance ,it may
be due to mutation in DHFRase .
 resistance with falciparum is common than vivax
46

47. Pharmacokinetics:
Slow & good absorption
Attains good concentration in organs
Metabolized & excreted in urine
t1/2: 4 days,prophylactically stays in blood – 2wks
Uses:
Suppressive treatment chloroquine resistant falciparum
Toxoplasmosis -high doses given
47

48. Adverse drug reactions of pyrimethamine:
Nausea, rashes ,megaloblastic anemia & granulocytopenia with
higher doses.
Sulfonamide – pyrimethamine
Supra additive synergism - sequential block
Faster acting against chloroquine resistant p.falciparum
Has long half life
In India - with artesunate for all falciparum cases
48

49. Fixed dose Combinations :
Pyrimethamine 25mg + sulfadoxine 500mg
Pyrimethamine 25mg + sulphamethopyrazine 500mg
Pyrimethamine 25mg +dapsone 100mg :
given in 2nd & 3rd trimester of pregnancy with folic acid
In resistance quinine given with these combination
49

50. ADR :
Exfoliative dermatitis, stevens johnson syndrome
Precautions
Avoided in pregnancy due to antifolate & teratogenic effects,
avoid in children
50

51. Primaquine
8 – Aminoquinoline
Radical cure : given with chloroquine
only agent active against dormant hepatic forms of vivax & ovale
Gametocidal action against all four species of plasmodium
Mechanism of action Primaquine:
Not clear, its converted & produces active oxygen interfere with
plasmodial mitochondrial function
Resistance induced among p.vivax
51

52. Pharmacokinetics of primaquine:
Well absorbed oral,
wide distribution
Half life 3-8h,peak :1-2hrs
Generates 3 active metabolite ,excreted in urine
Uses of primaquine
1.Radical cure
a)P.vivax & ovale :
Given in acute attack or throughout incubation period
prevents relapse
52

53. Prophylactically: before & after leaving the endemic area to eradicate
hepatic forms
 Effective vector control is possible or used in areas of low
transmission
b) Falciparum malaria:
 45mg with chloroquine or ACT used like gametocidal & cut down
transmission or where effective control is needed
53

54.  Primaquine cont..
2. AIDS:
 15mg/day with clindamycin 600mg TDS alternatively used
Adverse drug reaction of Primaquine
Therapeutic doses:
 Haemolysis & methaemoglobinaemia commonly seen in G6PD
deficiency
 Causes nausea, headache, epigastric pain &abdominal cramps on
empty stomach
 Rarely : leucopenia, leucocytosis & agranulocytosis
54

55. Precaution - Primaquine
G6-PD deficiency checked & blood counts repeated if >30mg of
Primaquine given
AVOID
In patient with haemolysis ,Rheumatoid arthritis & SLE
55

56. Tafenoquine
Newer 8-aminoquinolone single dose for vivax hypnozoites
 Some activity was seen against asexual erythrocytic stage of
P.vivax,P.falciparum & chloroquine resistant state
Tafenoquine pharmacokinetics:
 With long half life 16-19 days, acts lasting upto a week
 Causes haemolysis in G6PD deficient patient, anaemia,
haemolysis & methaemoglobinaemia reported
 Its undergoing phase-3 trial in India with 3 day chloroquine to
prevent relapse in vivax ,likely to be single dose radical cure
56

57. Tetracyclines & Doxycyclins
 Erythrocytic schizonts are inhibited by all malarial parasite
 Tetracycline used in combination with quinine in treatment of
chloroquine resistant as well vivax malaria
 Avoid in children & pregnant women
 Dose: 250mg QID or Doxycycline 100mg OD equally effective
57

58.  Doxycycline cont..
 Doxycycline used in places where high resistance present
 200mg Doxycycline combined with artesunate to treat
mefloquine/chloroquine/s-p resistant malaria
 100mg/day of Doxycycline used 2nd line prophylactic for short
travels to chloroquine resistant P.falciparum
Adverse effects:
 Photosensitivity & suprainfection
58

59. Clindamycin:
Slow erythrocytic schizontocide, bacteriostatic
With Quinine used in treatment of resistant P.Falciparum
Its used where tetracyclines can not be used in pregnancy &
children less than 8 years old
59

60.  Derived from plant Artemisia annua – (Chinese traditional
medicines)
 Its sesquiterpine lactone endoperoxide, poorly soluble in oil &
water-used orally/rectally
Other compounds :
 Dihydroartemisinin (oral)
 Artemether(oral or i.m) & artesunate(oral/rectal/i.v/i.m)
 Arteether –(i.m) produced in India in 1990
60

61.  Arterolone - (oral) synthetic compound are developed
Spectrum Actions:
 Rapidly acting erythrocytic schizonticides clears parasite in
<48hrs
 Safe & 10-100 times potent compared to other antimalarials
 Active against P.falciparum resistant to all other anti malarial
drugs as well sensitive strains
61

62. Artemisinin comp cont…
 They are lethal to early gamete stage by reducing number of
gametes
MOA:
 Endoperoxide moiety produces carbon centered radicals by
intramolecular rearrangement which modify & damages malarial
proteins
 High reacted free radicals inhibit plasmodial sarcoplasmic
endoplasmic calcium ATPase –(pf ATP6)
 Resistance ↓s response & combination of drug with different
mechanism & longer acting drugs given with these drugs in 3
days course will solve the problem
62

63. Artemisinin comp cont…
Pharmacokinetics
ORAL absorption of Artesunate -rapid peak of <60min, causes
auto induction by CYP2B6 & CYP3A4
Artemether absorption is delayed 2-4h, to increase absorption taken
with food,CYP3A4 metabolism extends ½ life to 3-10h
Both these drugs get converted to dihydroartemisinin
presystemically
63

64.  Artemisinin comp cont…
 Half life is 1-2h
 Artemisinin and dihydroartemisinin extensively metabolised little
amount excreted in urine
 Arteether long half life 24h can be used alone in 3days with very
low recrudescence
 Dose:12mg of total oral dose for both children & adults in which
4mg/kg given on first day followed by 2mg/kg for 4 days(5
daystreatment)
64

65. Artemisinin comp cont…
Parenteral:
Artesunate-120mg i.v/i.m on first day followed by 60gm for next 4
days by same route
Artemether: 2mg/kg for 5 days
Arteether: for complicated malaria in adults i.m 150mg daily is
preferred since it has long t1/2 24h its used in 3 day course but
WHO recommends 5 day Course
Uses
For uncomplicated falciparum malaria,Chloroquine resistant &
sensitive strains:FDC of ACT used
65

66.  in vivax where Chloroquine is resistant & Quinine +
Clindamycin cannot be used Artemisinin (ACT) is used
 Single dose Primaquine used to kill circulating gametes after
ACT therapy
Severe complicated malaria:
 Parentral artemisinin high effective &lower mortality
 Quinine is used alternative when artemisinin cannot be used
 During pregnancy quinine i.v given during 1st trimester of
pregnancy since safety of artemisinin compounds not yet
proved
66

67. Adverse effects:
Mild :nausea, vomiting, abdominal pain, itching &drug fever
Headache, tinnitus, dizziness, bleeding, dark urine, S-T segment
changes, Q-T prolongation, first degree A-V block, transient
reticulopenia & leucopenia are rare
Halofantrine (phenanthrene methanol)
Not preferred due to erratic bioavailability & cardiotoxicity &
extensive cross resistance with MEFLOQUINE
It was used in multidrug resistant strain of both falciparum &
vivax,it’s a blood schizonticide
67

68. Lumefantrine
Belongs to the arylaminoalcohol
 has a similar mechanism of action it alters protein & nucleic
acid synthesis.
 racemic fluorine derivative developed in China.
It is only available in an oral preparation coformulated with
artemether.
This ACT is highly effective against multidrug resistant P.
falciparum.
68

69. Lumefantrine cont…
 orally active, long acting, highly effective blood schizonticide
Pharmacokinetics
 Its lipophilic ,absorption starts after 2hrs peaks 6-8h
 99%plasma protein bound
 Metabolized by CYP3A4
 ½ Life 4-6 days
 Taken with fatty diet to achieves adequate blood levels
Dose:
 480mg BD - 3days,adult & chidren >35kg 4tab given with
artemether 80mg BD
 Children 26-35 kg-3tab,16-25kg-2tab,5-15kg-1tab
69

70. Lumefantrine cont…
Uses:
In combination with artemether 20mg+lumefantrine 120mg in
one tab used as FDC
Both drugs prevent resistance
Decreases gametocyte number & prevents recrudescence
It achieves 99% cure rates
Adverse effects
Minor effects:
 Gastrointestinal disturbances, headache, dizziness rashes &
pruritis
Little Q-T prolongation seen
Avoided in pregnant & lactating women
70

71. Pyronaridine
Newer drug from Mepacrine developed in china
Mechanism similar to chloroquine
High effective erythrocytic schizonticide,effective against
chloroquine sensitive & resistant vivax & falciparum malaria
Slow onset & long duration of action, concentrated in RBC
Water soluble, t1/2 : 7days
Orally & parenterally used , well tolerated
At high dose used analgesic/anti pyretic
71

72.  Its used FDC with Artesunate in multi drug resistant falciparum
& vivax
 Clinical trial proves >95% success rate in India
 This ACT not approved for use in India
Adverse effects:
Abdominal pain, vomiting, headache, dizziness , loss of appetite,
palpitation
 Dose:
Artesunate 100-200mg(2-4mg/kg)+pyronaridine 300-600mg(6-
12mg/kg)/day-3days
72

73. Atovaquone:
 Hydroxy naphthoquinone antiparasitic drug active against all
Plasmodium species.
 Rapid acting erythrocytic schizontocide & inhibits pre-erythrocytic
stage of falciparum.
 Also active against pneumocystis jiroveci & Toxoplasma gondii
 combined with proguanil Where its resistant, reduces relapse &
which is synergistic.
 Collapses mitochondrial membrane interferes with cytochrome
electron transport.
73

74. Dosage
250 mg of atovaquone and 100 mg of proguanil hydrochloride for
adults. QID with food
Tablets containing 62.5 mg of atovaquone and 25 mg of
proguanil hydrochloride for paediatric use.
Given 3 days for uncomplicated chloroquine resistant falciparum
& vivax used in some countries but not in India
Uses:
Mild –mod malaria chloroquine & multi drug resistant
Can be used prophylactically by non immune travellers visiting
endemic areas,
74

75. In oppurtunistic infections, pneumonia, Toxoplasmosis & Babesiosis
Pharmacokinetics
poorly absorbed following oral administration can be improved by
taking the drug with fatty foods.
99% bound to plasma proteins and has plasma half-life of around
66–70 h due to enterohepatic recycling.

It is excreted in the faeces as unchanged drug
75

76. Adverse effects
Skin rashes, headache, fever, insomnia, nausea, diarrhoea,
vomiting, raised liver enzymes, hyponatraemia
Rarely: haematological disturbances.
Drug interactions
↓ plasma concentrations with Tetracycline and Acyclovir,
antidiarrhoeal drugs, Benzodiazepines, cephalosporins, laxatives,
Opioids and Paracetamol.
 Atovaquone ↓ the metabolism of zidovudine and cotrimoxazole.
it displace other highly protein-bound drugs from plasma-protein
binding sites.
76

77.  Antimalarial drugs alone – Resistance & fail to prevent malaria
 WHO :Acute uncomplicated resistant P.F malaria should be treated
only by combining one of the artemisinin compounds with another
effective erythrocyte schizontocide.
 Advantages of ACT over other antimalarials:
 Rapid clinical & parasitological cure.
 High cure rates, low relapse rate.
 No resistance.
 Good tolerability.

77

78. ACT regimens for uncomplicated falciparum malaria.
 1.Artesunate – mefloquine (AS/MQ)
Artesunate 100 mg BD (4 mg / kg / day) 3 days + Mefloquine
750 mg (15 mg / kg) on 2 nd day and 500 mg (10 mg / kg) on 3
rd day (total 25 mg / kg).
2.Artimether – lumefantrine (1:6)
Artemether (80 mg BD) + lumefantrine (480 mg BD) 3 DAYS

78

79.  Adult and child >35 kg :4 tab BD;
 child 25 – 35 kg : 3 Tabs bid;
 15 – 25 kg :2 tab BD;
 5 – 15 kg 1 tab BD, All for 3 days
Act reg cont…….
3.Artesunate – sulfadoxine + pyrimethamine
 Artesunate 100 mg BD (4 mg / kg / day ) 3 days +
 sulfadoxine 1500 mg (25 mg / kg) and
 pyrimethamine 75 mg (1.25 mg / kg) single dose
79

80. 4.Arterolane – Piperaquine.
Arterolane (as maleate)150mg+ Piperaquine750mg daily -3days
One capsule OD for 3 days
5. Dihydroartemisinin- Piperaquine(DHA/PPQ 1:8)
DHA120mg(2mg/kg)+piperaquine960mg(16mg/kg)daily for 3
days
6. Artesunate – Amodiaquine (AS/AQ)
Artesunate 200mg(4mg/kg)+Amodiaquine(10mg/kg)per day-3
days
80

81.  ACT regimen cont…
 Artesunate 25mg/50mg/100mg+Amodiaquine
67.5mg/135mg/270mg FDC approved in India
 7.Artesunate -Pyronaridine(1:3)
 Artesunate 100-200mg (2-4mg/kg) + pyronaridine 300-600mg(6-
12mg/kg)per day- 3 days.
 TREATMENT OF UNCOMPLICATED MALARIA
 a) Vivax (ovale,malariae) :
1. Chloroquine 600mg (10mg/kg base) followed by
300mg(5mg/kg)after 8hrs for next 2 days(total 25mg/kg over 3
days) + Primaquine 15mg(0.25mg/kg)daily -14days
81

82. ACT regimen cont…
In occasional case of chloroquine resistance:
 Quinine 600mg(10mg/kg)8hrly – 7days + Doxycycline 100mg daily
-7 days
or
 + Clindamycin 600mg 12hrly -7days
 +Primaquine (as above)
(or)
ACT based combination + primaquine (as above)
 B) Chloroquine - sensitive falciparum malaria
 Chloroquine(as above) + primaquine 45mg(0.75mg/kg)single dose
(gametocidal)
82

83. 1. Artesunate 100mg BD (4mg/kg/day) – 3 days + Sulfadoxine
1500mg(25mg/kg)+ Pyrimethamine 75mg (1.25mg/kg) single
dose
 Or
2. Artesunate 100mg BD(4mg/kg/day)- 3 days + Mefloquine
750mg(15mg/kg) on 2nd day & 500mg(10mg/kg) on 3rd day
or
 3. Artemether 80mg+ lumefantrine 480mg BD – 3 days(Child
25-35kg BW ¾ Dose;15-25 kg BW ½ dose;5-15 kg BW ¼ dose

83

84. (or)
4.Arterolane (as maleate) 150mg + Piperaquine 750mg OD – 3
days
Or
5. Quinine 600mg(10mg/kg)8hrly – 7 days + Doxycycline
100mg daily -7 days
Or
Clindamycin 600mg 12hrly -7 days
84

85.  Artesunate 2.4 mg/kg IV or i.m as a first dose followed by
2.4mg/kg after 12 & 24h then OD -7days switch over to 3 day Oral
ACT in between whenever patient can take & tolerate oral
medication
(or)
 2)Artemether 3.2 mg/kg IM on first day followed by 1.6 mg/kg
daily for seven days switchover to 3 days oral ACT inbetween
whenever patient can take & tolerate oral medication

 (Or)
85

86.  Arteether 3.2mg/kg i.M on the first day followed by 1.6mg/kg
daily for next 4 days switchover to 3 days oral act in between
whenever patient can take & tolerate oral medication
Or
 Quinine di hcl 20mg/kg loading dose diluted in 10ml/kg
5%dextrose/dextrose –saline infused i.V -4hrs,followed
10mg/kg(maintenance dose)i.V. Infusion over 4hrs(in
adults)or 2h(in children)every 8hrs until patient can swallow
switchover to oral quinine 10mg/kg 8hrly to complete 7 day
course
86

87.  Drugs Used in pregnancy:
 Proguanil with folic acid 5mg/day
 Chloroquine in usual doses
 Quinine in low dose –chloroquine resistant malaria
 high dose- induce labour
 Pyrimethamine + Dapsone -2nd & 3rd trimester with
folinic acid
 Chloroquine, quinine & proguanil safe but
pyrimethamine with folinic acid can be used
87

88. NEWER DRUGS
4(1H)-quinolone-3-diarylethers :
 selective potent inhibitors of the parasite's mitochondrial
cytochrome bc1 complex.
highly active against the human malaria parasites Plasmodium
falciparum and Plasmodium vivax.
They target both the liver and blood stages of the parasite as well
as gametocytes, the zygote, the ookinete, and the oocyst.
88

89.  preclinical candidate, ELQ-300 has good oral bioavailability at
efficacious doses in mice
 Metabolically stable
 highly active in blocking transmission in rodent models of malaria.
 Given its predicted low dose in patients and its predicted long half-life,
ELQ-300 has potential as a new drug for the treatment,
prevention, and, ultimately, eradication of human malaria.
89

90. A Phase III trial began in May 2009 and has completed
enrolment in 2011
are expected to become available to WHO in 2014-2015.
evaluated as an addition to, not a replacement for, existing
preventive, diagnostic and treatment measures.
The need for long-lasting insecticidal nets, rapid diagnostic tests
and artemisinin-based combination therapies will continue
90

91. References :
- Pharmacological basis of Therapeutics – Goodman & Gilman
12th Edition
- Principles of pharmacology – HL Sharma & KK sharma 2nd
edition
- Text book of pharmacology – K. D. Tripathi.7th Edition
- Pharmacology & Therapeutics - R.S.Satoskar -Twentieth second
Edition.
91

92.  www.ncbi.nlm.nih.gov/pubmed
 www. ranbaxy.Com
 www.who.int/malaria/areas/vaccine/en.
92

93. 93
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