Malaria treatment

1. Pharmacotherapy of Malaria
Dr Ritu Budania,
MBBS, MD

2. Malaria
 Protozoal disease
Plasmodium
infected female anopheles mosquito

3. Tropical ,subtropical countries

4. WHO estimates
 300-500 million cases year
 > 1 million death
India- NVBDCP- 1.5 million confirmed cases

5. Pathogenesis
5

6. Classification of Anti Malarial Agents: 1 –
Chemical Structure
 4-Aminoquinolines : Chloroquine, Amodiaquine
 8-Aminoquinoline: Primaquine, Bulaquine
 Cinchona alkaloid : Quinine
 Sesquiterpine lactones: Artesunate, Arteether, Artemether
 Biguanides: Proguanil
 Diaminopyrimidine : Pyremethamine
 Quinoline methanol : Mefloquine
 Sulfonamides : Sulfadoxine
Sulfamethopyrazine
 Phenanthrene methanol : Halofantrine
 Tetracycline: Doxycycline,
 Acridine : Mepacrine
 Naphthoquinone Atovaquone
6

8. Classification- Stage of Parasite
affected
Stage Drugs
Blood schizonticidal drugs Erythrocytic phase
Terminates clinical illness
Chloroquine,
Artemissin,
Quinine,
Atovaquone,
Tissue schizonticidal drugs Tissue form of plasmodium Primaquine,
Pyrimethamine
Proguanil
Tetracycline
Gametocidal drugs Destroy sexual forms of
parasite
Prevent transmission to
mosquiotes
Primaquine
Quinine
Hypnozoiticidal Destroy persistent liver
stages of P vivax , P ovale
Primaquine

9. Target of Existing therapies
Target
location
Pathway/
mechanism
Target
molecule
Existing
therapies
Cytosol Folate
metabolism
DHF reductase
DHP synthetase
Pyrimethamine
Proguanil
Sulfadoxine
Food vacuole Heme
polymerization
Free radical
generation
Hemozoin
Unknown
Aminoquinolines
Artemisinin
Mitochondrion Electron transport Cyt. c
oxidoreductase
Atovaquone
9

10. Anti- Malarial Drugs

11. Chloroquine Sulfa/Pyri Quinine Mefloquine
Artemissin
Efficacy +++ ++ +++ +++ ++++
Onset of
action
rapid slow rapid rapid fastest
Use Chemophrophyla
xis
-Treatment of
Chloroquine
sensitive malaria
Uncomplicat-
ed
resistant
P. falciparum
Only for
resistant
P.
falciparum
severe
malaria
cerebral
malaria
Only for
uncomplica
ted,
resistant
P.
falciparum
-resistant
P. falciparum.
- life threatening
complications of P.
falciparum due to
its rapid action
- severe malaria

12. Chloroquine Sulfa -pyr Quinine Mefloquine Artemissin
ADR GI ADR
IV-
Hypotension
,arrythmias
Retinal
damage
Steven
Johnson
Megaloblast
ic anemia
-Cinchonism
-Hypoglycemia
-Hypotension
-Arrhythmias
Neuropsychiatric
symptoms
-Sinus
bradycardia
Safe
A-V block
Reticulopenia
Transient
leucopenia
Contraindic
ation
-Psoriasis,
porphyrias
-Allergy to
sulfa drugs
-Prior
hypersensitivit
y
-Epilepsy
-Psychosis
-Heart block
-
Special
points
Not given
parenterally
in children
-5 % glucose
solution
-Infusion
-Not rapid iv
-Not given
parenterally
Not given with-
Halofantrine,
Beta blockers
Do not kill
hypnozoites
Cost cheap cheap moderate expensive expensive

13. Primaquine
• Radical cure
• prevents relapse in P vivax and P ovale malaria
• Hemolytic anemias- G-6PD status should be evaluated
• Not given parenterally- causes hypotension
• Contraindicated in Pregnancy and infants
13

14. Antimalarial Combination Therapy
 Simultaneous use of two or more blood schizontocidal drugs
with independent modes of action
 more effective than monotherapy
 Higher cure rates
 reduce the development of resistance
 decrease transmission of drug-resistant parasites.
14

15. Combination therapies recommended by
WHO
• Artemether – Lumefanterine
• Artesunate- Amodiaquine
• Artesunate – Mefloquine
• Artesunate- SP
• Quinine - Tetracyclines/ Clindamycin
Oral Artemissin monotherapy is banned in
India
-never orally as monotherapy for
uncomplicated malaria
.

16. Guidelines for
treatment of Malaria -2011

17. Early diagnosis and treatment of cases of malaria aims
at:
• Complete cure
• Prevention of progression of uncomplicated malaria to
severe disease
• Prevention of deaths
• Interruption of transmission
• Minimizing risk of selection and spread of drug
resistant parasites

18. Treatment of P. vivax Malaria
• Chloroquine 25 mg/kg for 3 days
• Primaquine 0.25 mg/kg for 14 days

19. Treatment of P. falciparum cases
• Artemisinin based Combination Therapy (ACT)
Artesunate 4 mg/kg for 3 days
Sulfadoxine (25 mg/kg body weight)-
Pyrimethamine (1.25 mg/kg body weight) on Day 0
• Primaquine 0.75mg/kg on Day 2

20. Treatment of malaria in pregnancy
 P. falciparum:
• 1st Trimester: Quinine
• 2nd & 3rd Trimester: ACT
 P vivax: Chloroquine
Note: Primaquine is
contraindicated in pregnant woman
20

21. Treatment based on clinical criteria
without laboratory confirmation
• Suspected cases – “clinical malaria”
Chloroquine 25 mg/kg for 3 days
• Once the parasitological diagnosis is
available, appropriate treatment as per the
species

22. General recommendations for the
management of uncomplicated
malaria
• Avoid starting treatment on an empty
stomach.
• if vomiting occurs within 30 minute- repeat
the dose .
• Ask the patient to report back- if there is no
improvement after 48 hours or if the situation
deteriorates.

23. Treatment of severe malaria
• Impaired consciousness/coma
• Repeated generalized convulsions
• Renal failure (Serum Creatinine >3 mg/dl)
• Jaundice (Serum Bilirubin >3 mg/dl)
• Severe anaemia (Hb <5 g/dl)
• Pulmonary oedema/acute respiratory distress syndrome
• Hypoglycaemia (Plasma Glucose <40 mg/dl)
• Metabolic acidosis
• Circulatory collapse/shock (Systolic BP <80 mm Hg, <50 mm Hg in
children)
• Abnormal bleeding and Disseminated intravascular coagu- lation
(DIC)
• Haemoglobinuria
• Hyperpyrexia (Temperature >106 F or >42C)
• Hyperparasitaemia
23

24.  Medical emergency
 Parenteral treatment
 Parenteral Artemisinin derivatives or Quinine should be used irrespective of chloroquine sensitivity.
Artesunate 2.4 mg/kg i.v. or i.m. at admission 12 & 24hr
, then once a day
or
Artemether 3.2 mg/kg i.m. given on admission then
1.6 mg/kg per day;
or
Quinine 20 mg /kg on admission (i.v. infusion in 5 %
dextrose over 4 hours)
then maintenance dose 10 mg/kg every 8 hrly .
Arteether 150 mg daily i.m. for 3 days in adults only
(not recommended for children).
Parenteral treatment should be given for minimum of 24
hours once started

25. • Patients receiving parenteral Quinine should
receive-
oral Quinine 10 mg/kg three times a day to
complete a course of 7 days
Doxycycline 3 mg/ kg per day for 7 days.
• Doxycycline is contraindicated in pregnant
women and children under 8 years of age
• Instead, Clindamycin 10 mg/kg 12 hourly for 7
days should be used

26. Chemoprophylaxis
• Non immune travellers
• Army units
• Migrant workers

27. Chemoprophylaxis
• Short-term chemoprophylaxis (less than 6 weeks)
Doxycycline: 100 mg daily in adults
1.5 mg/kg for children> 8 years old
The drug should be started 2 days before travel and
continued for 4 weeks after leaving the malarious area.
• Long-term chemoprophylaxis (more than 6 weeks)
Mefloquine: 5 mg/kg (up to 250 mg) weekly
administered two weeks before, during and
four weeks after leaving the area.
27

29. Malaria Vaccine
Is Malaria vaccine feasible?
Current clinical studies have shown that new candidate
vaccines can induce complete protection against malaria
infection.
Complete protection against malaria can be induced by
infecting volunteers with irradiated malaria parasites.
People living in endemic areas who have been multiply exposed
to malaria develop immunity against severe malaria disease.
Antibodies purified from life-long residents of endemic areas
can be transferred into other individuals and can confer some
protection against the effects of malaria infection.

30. Leading transmission blocking antigens
(Sexual Stage)
Antigen Strengths Weakness
Pfs25/Pvs25
Pfs28/Pvs28
- Both antigens
cloned and expressed
- induces complete
transmission-blocking in model
systems
Not expressed in the
vertebrate host,
not subject to natural
boosting following
vaccination
Pfs48/45 -Monoclonal antibodies
completely block transmission
-Expressed on the gametocyte so
boosting of antibody response a
possibility.
------------------
Pfs230 -Monoclonal antibodies
completely block transmission
-compliment mediated antiparasite
activity
-Expressed on the gametocyte
A very large molecule, so
unclear which part/s to
make.
These antigen vaccines are currently in phase I/Preclinical stage.

31. New Malarial Vaccines Status
Parasite
stage
Vaccine Stage of
Development
Pre
Erythrocytic
Stage
CSP C-ter peptide + Montanide ISA 720 Phase Ib
ICC-1132: Hybrid CSP multiepitope-HBc VLPs Phase II
RTS,S: Hybrid P. falciparum CSP -HBsAg
particles + AS02 adjuvant
Phase IIb
DNA vaccines (including MuStDO-5:
CSP/LSA-1/ LSA-3/EXP1/TRAP)
Phase I
Live recombinant FPV- or MVA-CSP
+ LSA-1 epitope
Phase Ib
Live recombinant MVA-multiepitope
string + TRAP
Phase Ib
LSA-3 (long peptides; lipopeptide;
recombinant)
Phase Ia

32. New Malarial Vaccines Status
Parasite
stage
Vaccine Stage of
Development
Blood Stage PfCP 2.9: MSP-1-AMA-1 fusion
protein (yeast) + Montanide ISA 720
Phase I
MSP-3 long peptides Phase Ib
GLURP long peptide Phase I
MSP-3-GLURP hybrid long peptide +
Montanide ISA 720
Phase I
Combination B: MSP-1, -2, RESA +
Montanide
Phase II
SE36 Phase I
MSP-4, -5 Preclinical

33. Drugs reversing Chloroquine Resistance >> >
Experimental
• Ca-Channel Blockers: Verapamil
• Vitamin E : Deficiency may afford protecton
• Penfluridol : Reverses Mefloquine resistance

34. Summary
• Antigen variability- vaccine development
• Resistance in plasmodium
• Insecticide resistance
• Judicious use of Anti malarials
• Early diagnosis and treatment

35. References
• Goodman & Gilman’s 12th edition
• K.D.Tripathi 6th edition
• KK Sharma 2nd edition
• Basic & clinical Pharmacology Katzung
• Guidelines for diagnosis and treatment of Malaria 2011 National Vector
Borne Disease Control Programme, National Institute
of Malaria Research