Malaria, its pathogenesis, distribution and pharmacotherapy

1. Treatment & Recent Advances
in
Management of Malaria
Dr. Karabi Adak,
MBBS, MD

2. History
• In 20th century, malaria claimed between 150 million
and 300 million lives, accounting for 2 to 5 percent of all
deaths (Carter and Mendis, 2002).
• Victims have included Neolithic dwellers, early Chinese
and Greeks, princes and paupers.
• Chief sufferers today are the poor of sub-Saharan
Africa, Asia, the Amazon basin, and other tropical
regions

3. History
• 40 percent of the world's population still lives in areas
where malaria is transmitted.
• Sir Ronald Ross received nobel prize in 1902 for his work
on transmission of malaria
• Golgi was awarded the Nobel Prize in 1906 for unrelated
studies of the central nervous system.
• One year later, Laveran received the Nobel Prize for
discovering the single-celled protozoan that caused
malaria.

5. Estimated Malaria cases in 7 states
(contribute 90% of cases)

6. Malaria
• Protozoal infection, Vector borne disease
• Unsuccessful eradication attempts, resurgence towards the end of
20th century*
• 120 species, 5 known to affect humans.
*Ashley EA, et al., Malaria. Lancet. 2018 Apr 21;391(10130):1608-1621.

7. TYPES of MALARIAL PARASITE
Plasmodium falciparum sequester in critical organs, produces
high level of parasitemia
Plasmodium vivax produces milder disease, but can be
severe
Plasmodium ovale understudied but severity similar to P.
Vivax
Plasmodium malariae morphologically indistinguishable species
Plasmodium knowlesi encountered in southeast Asia that can
cause severe malaria.

8. Biology of Malarial Parasite
Lippincott’s Illustrated Reviews

9. Clinical Presentation
non-specific, includes
• fever
• chills
• body-aches
• headache
• cough
• diarrhoea,
• clinical diagnosis
unreliable.
Uncomplicated malaria
Severe malaria
*WHO 2015 severity
criteria

10. Diagnostic tests for malaria
Microscopy
based
Molecular
based
Molecular
based
Immnology
Immunology
based
sed
Rapid
Diagnostic
Test (RDT)
based
gnostic Test
(RDT)

11. Clinical classification of antimalarial drugs
1. True causal prophylactics- no drug available
2. Causal prophylactics- primaquine, pyrimethamine and proguanil
3. Suppressives-
(a) Rapidly acting: quinine, 4-aminoquinolines, mefloquine,
artemisinin, atovaquone
(b) Slowly acting: proguanil, pyrimethamine, sulfadoxine and
tetracycline
4. Radical curatives- primaquine and proguanil
5. Gametocytocidal drugs- chloroquine, quinine, artesunate, primaquine

12. Chemical classification of anti-malarial drugs
1. Cinchona alkaloids: Quinine,
Quinidine
2. Quinoline derivatives:
– 4-Aminoquinolines:
Chloroquine, Amodiaquine,
Pyronaridine
– 8-Aminoquinolines:
Primaquine, Tafenoquine,
Bulaquine.
– Quinoline methanol:
Mefloquine
3. Phenanthrene methanol:
Halofantrine, Lumefantrine
4. Antifolates:
a. Biguanides: Proguanil
b. Diaminopyrimidines:
Pyrimethamine
c. Sulfonamides :
Sulfadoxine
5. Artemisinin compounds:
Artesunate, Artether, Artemether
6. Antimicrobials:
Doxycycline, Clindamycin,
Atovaquone

13. Quinine
MOA: General
protoplasmic poison,
depresses various
enzymatic processes
Reduces ciliary activity
Inhibits phagocytosis
and growth of
fibroblasts
• Therapeutic uses:
• Malaria
• Myotonia congenita
• Cramps

14. Quinine
Pharmacological actions:
• Cinchonism
• Cardiovascular toxicity
• Blackwater fever
• Hypoglycemia
Adverse Effects:
• Antimalarial action
• Local irritant action
• Action on GIT
• Cardiovascular actions
• Analgesic and antipyretic
• Crosses BBB and placental barrier

15. Chloroquine
oxidative damageoxidative damage to organelles of
parasite to organelles of parasites
binds binds to released heme, thus preventing its
polymerisation
MOA: beinbeing basic, concentratesin the acidic
lysosomesg basic, concentrates in the acidic lysosomes

16. Chloroquine
Pharmacological actions:
• Antimalarial activity
• Other antiparasitic actions
• CVS
• Miscellaneous actions
Therapeutic uses:
• Malaria
• Amoebiasis,Giardiasis,Clonorchis
sinensis
• Rheumatoid arthritis
• Auto-immune diseases
• DLE
Adverse reactions:
• Intolerance
• Eye
• Central Nervous System
• Cardiovascular System

17. Primaquine
MOA: not precisely known
Might be generating toxins
Might interfere with electron transport in the
parasite

18. Primaquine
Effective Against:
• The persistent tissue forms
of P. vivax
• The pre-erythrocytic
(hepatic) and sexual forms
(gametocytes) of all species
of human malarial parasites
• Weak schizonticidal activity
against P. vivax, no effect
on the schizonts of P.
falciparum
Adverse reactions:
• GIT
• Hemopoetic
• Hemolysis

19. Mefloquine
• Acts on the erythrocytic stage
• Is highly effective in a single
dose against P. falciparum
including chloroquine resistant
and MDR strains
• Can be given 12 hours after
the last dose of quinine
• Has no action on the persistent
tissue forms
Adverse reactions:
• GIT
• Neuropsychiatric disturbances
• CVS
• Teratogenicity
• Skin reaction
• Hepatitis
• Blood dyscrasias

20. Halofantrine
• Erythrocytic schizonticide,
chloroquine sensitive strains of
P. falciparum
• Effective against strains
resistant to chloroquine,
pyrimethamine and quinine
• Used in ACT
• Used where resistance to
monotherapies
Adverse reactions:
• GIT
• Prolongation of QT interval
• Fatal ventricular arrhythmias
(should not be used in patients
receiving quinine, chloroquine
or quinidine, antidepressants
and antipsychotics)
• Not suitable for prophylaxis

21. Proguanil
• Prodrug
• Folinic acid prevents
completion of
schizogony
• Sulfonamides prevent
conversion of PABA into
folic acid  synergise
with effect of proguanil.
MOA: conversion to cycloguanil, in
tconversion to cycloguanil, in the
human body.
he human body.
Binds to dihydrofolate
reductase
Folic acid to folinic acid
formation inhibited
IncompletIncomplete
schizogonye schizogony

22. Proguanil
Uses:
• Effective schizonticide against
both P. vivax and P. Falciparum
• Against primary pre-
erythrocytic forms of P.
falciparum, and for causal
prophylaxis of falciparum
malaria
• Gametocidal
• Acute attack
Adverse Reactions:
• GI disturbances
• Stomatitis, and mouth
ulcers
• Leucopenia
• Megaloblastic anemia

23. Pyrimethamine
• Same MOA like proguanil,
more potent
• Selectively binds to DHF
reductase
• Antimalarial activity
enhanced with sulfonamides
(DHF reductase inhibitor)
• Cross resistance with
proguanil
Therapeutic uses:
• Malaria
• Toxoplasmosis
• Polycythemia vera
Adverse effects:
• GI upset
• Ataxia
• Megaloblastic anemia
• Combined with sufadoxine
for prophylaxis can cause
SJS

24. Artemisinin compounds
• Obtained from the
Chinese plant Artemisia
annuta (Qinghaosu,
sweet worm wood)
• Artesunate (water
soluble), artether and
artemether (both lipid
soluble).
Resultant free radicals damage
parasitic proteins
Intraparasitic heme iron catalyses
cleavage of endoperoxide bridge in
artemisinin.
MOA: Covalently binds to parasitic
proteins.

25. Artemisinin compounds
• Schizonticides against all
malarial parasites
• No effect on the hepatic
stage.
• Recrudescence may occur.
• Also useful in cerebral malaria
Adverse effects:
• Nausea, vomiting, abdominal
pain, anorexia and
leucopenia.
• Higher doses may produce
bradycardia, prolongation of
PR and QT and transient
increase in SGOT/SGPT.
• C/I- first trimester of
pregnancy, lactation, and in
immunocompromised
patients.

26. Antimicrobials
• DOXYCYCLINE: slow but potent action against the
blood schizonts and the primary exo-erythrocytic forms
of P. falciparum, including those resistant to
chloroquine and proguanil
• CLINDAMYCIN: has also been found useful in
combination with other drugs .

27. Antimicrobials
• ATOVAQUONE:
– Highly lipophilic, hydroxynaphthoquinone compound
– Potent activity (in animal models) against P. jiroveci,
Plasmodia, T.gondii, Toxoplasma
– MOA: selsctively interferes with mitochondrial electron
transport in susceptible parasites
– Proguanil potentiates antimalarial activity of atovaquone
– Adverse reactions: Fever, vomiting, anorexia, headache,
diarrhoea, dose related maculopapular rash, anemia and
neutropenia.

28. Treatment of chloroquine sensitive acute malaria
In patients who can take orally:
• Chloroquine (base) 600 mg followed 6 hours later by 300 mg
on day one; 300 mg once daily on days two and three.
OR
• Amodiaquine (base) 600 mg followed by 200 mg (base) on day
one; 400 mg once a day on days two and three.
OR
• Quinine (salt) 300 mg tablets, 6 (1.8 g) tablets daily for three
days, followed by 4 (1.2g) tablets daily for the next 5–10 days.

29. Treatment of chloroquine sensitive acute
malaria
In patients who cannot take orally:
• Chloroquine IM 2.5 mg/kg every 4 hours or 3.5 mg/kg every 6
hours (total dose not to exceed 25 mg/kg base)
OR
• Chloroquine IV 10 mg/kg base over 4 hours, followed by 5
mg/kg base (given in a 2 hour infusion) every 12 hours (total
dose not to exceed 25/mg/kg base)

30. Treatment of chloroquine resistant malaria
In patients who can take orally:
• Sodium artesunate 100 mg orally 12 hourly for 3 days
plus sulphadoxine (500 mg)+ pyrimethamine (25 mg) 3 tabs
as single dose on day one
OR
• Sodium artesunate 100 mg orally 12 hourly for 3 days
plus mefloquine 750 mg on day 2 and then 500 mg on day 3
OR
• Artmether (20 mg) + lumefantrine (120 mg) 4 tabs twice
daily for 3 days

31. Treatment of chloroquine resistant malaria
OR
• Quinine 600 mg orally t.i.d. for 5 days followed by
sulphadoxine-pyrimethamine 3 tablets as single dose
OR
• Quinine 600 mg t.i.d. + doxycycline 100 mg
b.i.d./clindamycin 10 mg/kg b.i.d. for 7 days
OR
• Sodium artesunate 100 mg orally + doxycycline 100 mg
b.i.d./clindamycin 10 mg/kg b.i.d. for 7 days
OR
• Atovaquone 250 mg+ proguanil 100 mg combination; 4
tablets (single dose) daily for 3 days

32. Treatment of chloroquine resistant malaria
In patients who cannot take orally:
• Quinine hydrochloride by i.v. infusion: 20 mg/kg in 500 mL of 5%
dextrose-saline over 4 h; followed by 10 mg/kg infused over 2 h,
every 8 h, until the patient is able to swallow and parasite density is
<1%. Complete the therapy with oral quinine 600 mg t.i.d. till total
therapy is of 7 days AND Tetracycline 250 mg i.m. 6 hourly until
patients start taking orally, followed by doxycycline 100 mg b.i.d. till
total of 7 days
OR
• Artemether or arteether i.m. AND Doxycycline OR Clindamycin

33. Drug Combinations for MDR falciparum
• Artesunate + SP/ mefloquine/ amodiaquine
• Artemether + lumefantrine
• SP + CQ/ amodiaquine/ quinine/mefloquine
• Quinine+ tetracycline/clindamycine
• Atovaquone + proguanil
• Sulphadoxine + pyrimethamine

34. Treatment in Pregnancy
•In 1st trimester:
✓ CQ for uncomplicated PV
✓ Quinine (PO or IV infusion) + Clindamycin x 7 d
✓ If quinine NA, use Artemisinin as lifesaving
• In 2nd & 3rd trimesters:
✓ Artemisinin (ACT or parenteral)
✓ Mefloquine
• PQ, Tafenoquine & Doxy are C/I

35. Artemisinin resistance- Major threat
• Widely prevalent in Southeast Asia
• Specific genetic K13-propeller mutations identified*
• ↑ parasite survival and ↑ resistance development to partner
drugs (piperaquine)
*Straimer J, et al. Drug resistance. K13-propeller mutations confer artemisinin
resistance in Plasmodium falciparum clinical isolates. Science.
2015;347(6220):428-431.

36. Artemisinin resistance- Major threat
Newer combinations -
• Pyronaridine-artesunate and Dihydroartemisinin-piperaquine
(DP)*
• 50% t/t failure with D-P in South-east Asia
• Triple Artemisinin-based Combination Therapies (TACT)
✓ D-P + mefloquine
✓ Artemether-lumefantrine (A-L) + amodiaquine
*The West African Network for Clinical Trials of
Antimalarial Drugs (WANECAM)

37. Chemoprophylaxis
R. S. Satoskar 26th edition

38. Newer Antimalarial Drugs
1. KAE609 (Cipargamin)
• A new synthetic antimalarial spiroindolone analogue.
• Antimalarial activity against asexual and sexual stages of
Plasmodium falciparum.
• Targets plasma membrane Na+-ATPase
2. Artemisone
• A drug in Phase II trials
• 10 times more potent than artesunate in vitro
• 4–10 times more potent in mice

39. Newer Antimalarial Drugs
3. Synthetic peroxides (first-generation ozonide OZ277)
• Arterolane
• Inhibits the growth of chloroquine-resistant (K1) and
chloroquine-sensitive (NF54) parasite strains with an IC50 =
1.6–1.8 nm
4. Methylene blue
• Approved injectable monoamine oxidase inhibitor for
methemoglobinemia
• Abolishes P. falciparum transmission to mosquitoes

40. Malaria Vaccine
1. The RTS,S vaccine
• Developed by GlaxoSmithKline (GSK)
• Stops Plasmodium falciparum malaria parasite entering the liver
• The phase 3 trial between 2009 and 2014, involving 15 000 children
and infants across seven sub-Saharan African countries
• Vaccine could prevent four in ten cases of malaria and three in ten
severe cases among children who received all four doses.
• Children require three doses at 1-month intervals with a final dose
20 months after the first.
2. The PfSPZ vaccine
• Sanaria have developed which had a protective efficacy of 48·3% in
an early phase 2017 clinical trial

41. Thank You