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TREATMENT OF MALARIA
Dr Roto Robo

OBJECTIVES AND USE OF ANTIMALARIALS
1. To prevent & treat clinical attack of malaria.
2. To completely eradicate the parasite from patient’s body.
3. To reduce the human reservoir of infection- to cut down
transmission to mosquito.
4. To minimize risk of spread of drug resistant parasites by use of
effective drugs in appropriate dosage by everyone.
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CLASSIFICATION OF ANTIMALARIAL DRUGS
1. Cinchona Alkaloid – Quinine, Quinidine
2. 4-Aminoquinolines – Chloroquine, Amodiaquine, Piperaquine
3. Diaminopyrimidines – Pyrimethamine
4. 8-Aminoquinoline – Primaquine, bulaquine
5. Sulfonamides & Sulfone – Sulfadoxine, sulfamethopyrazine,
Dapsone
6. Sesquiterpine Lactones – Artesunate, artemeter, arteether
7. Quinoline -Methanol – Mefloquine
8. Tetracyclines – Tetracycline, Doxycycline
9. Amino Alcohols – Halofantrine, Lumefantrine
10. Mannich base – Pyronaridine
11. Naphthoquinone – Atorvaquone
12. Biguanides – Proguanil, chlorproguanil
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MALARIAL TRANSMISSION CYCLE
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 CHLOROQUINE RESISTANCE
• Slow in P. Vivax
• P. Falciparum acquired significant resistance(NE region).
 MOR – Mutations in pfcrt > decreased ability of parasite to
accumulate chloroquine > easy leak out of vacuole.
 PHARMACOKINETICS
• Absorption – 1. orally - excellent
2. i.m. injection - good
• Large volume of distribution due to extensive tissue binding.
• Selective accumulation in retina > ocular toxicity in long use.
• Partly metabolized by liver & slowly excreted in urine.
• Early plasma t1/2 varies 3-10 days.
Terminal plasma t1/2 of 1-2 months.
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 SIDE EFFECTS
• GIT - nausea, vomiting, epigastric pain
• EYE - ↓ vision & difficulty in accomodation
• ENT - ↓ hearing
• CVS - hypotension, cardiac depression, arrythmias.
• CNS – convulsion, headache.
• Others - rashes, photo allergy, mental disturbances, myopathy ,
graying of hair.
 CAUTIONS
• Liver damage, severe git, CNS & haematological diseases.
• Not to be co administered with mefloquine, amiodarone and
other antiarrhythmics.
 In pregnancy - no abortifacient or teratogenic.
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QUININE
• Levorotatory alkaloid from cinchona bark.
• d-isomer quinidine used as an anti arrhythmic.
• Erythrocytic schizontocide for all the species of plasmodia.
• Less effective & more toxic than chloroquine.
• No pre- & exoerythrocytic action but kills vivax gametes.
• MOA ≈ chloroquine.
• Oral absorption – rapid & complete
• 90% plasma bound.
• Large fraction of dose metabolized in the liver.
• Plasma t1/2 (a) Malaria - 16hrs
(b) Healthy - 11hrs
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 SIDE EFFECTS
• Hypoglycemia – common major toxicity.
• Cinchonism - tinnitus, difficulty in hearing, visual defects,
nausea, vomiting, diarrhea, headache, vertigo, mental
confusion, flushing, marked perspiration, postural hypotension,
QTc interval prolongation.
• Other major rare s/e – hypotension, blindness, deafness,
cardiac arrhythmias, thrombocytopenia, hemolysis, HUS,
vasculitis, cholestatic hepatitis, neuromuscular paralysis.
• On rapid i.v. - hypotension, cardiac arrhythmias > die
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Pyrimethamine
• MOA – inhibitor of plasmodial DHFRase
• High selective affinity for plasmodial enzyme(≈2000 times >
mammalian enzyme)
• Slow but long acting erythrocytic schizontocide
• No pre- & exoerythrocytic action
 Good oral but variable i.m. absorption.
 Plasma t1/2 of 4 days.
 Prophylactic conc. remain in blood for 2 wks.
 SIDE EFFECTS
 Megaloblastic anemia, granulocytopenia
 Folate deficiency rare
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SULFONAMIDE
• SULFADOXINE and SULFAMETHOPYRAZINE –
ultra long acting but attain low blood conc.
• They are able to synergise with pyrimethamine.
• Combination has potential to cause serious adverse effects –
exfoliative dermatitis, SJS etc.
• Contraindicated – infant & patient allergic to sulfonamide.
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PRIMAQUINE
• Poor erythrocytic schizontocide – weak action on Pv and
blood form of Pf totally insensitive.
• Eradicates hepatic forms of Pv & P ovale.
• Kills all stages of gametocyte development of Pf.
 MECHANISM OF ACTION
1. Generating reactive oxygen free radicals or
2. By interfering with the electron transport in the parasite.
• Complete oral absorption, Plasma t1/2 of 7 hrs
 SIDE EFFECTS
• Most imprt toxic potential is dose related – hemolysis,
methaemoglobinaemia, tachypnea & cyanosis(oxidant property)
• Normal individual doses < 60mg – little hemolysis but
pt with G-6-PD deficiency even 15-30 mg/day. 15

MEFLOQUINE
• Fast acting(relative) erythrocytic schizontocide against
chloroquine sensitive as well as resistant plasmodia.
• Due to long t1/2 (14-20 days) chances of selection of resistant
strains are high.
• Its resistance confer cross resistance to quinine & halofantrine.
• MOA ≈ quinine
• Oral absorption is good but slow.
• Metabolized in liver & secreted in bile.
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 SIDE EFFECTS
• nausea, vomiting, diarrhea, abdominal pain, sinus bradycardia.
• Dose related neuropsychiatric reactions – disturbed sense of
balance, ataxia, errors in operating machinery, strange dreams,
anxiety, hallucinations, rarely convulsion.
• It is safe during pregnancy but avoided in 1st trimester.
 INTERACTIONS
• Co administration with halofantrine, quinidine/quinine
> QTc prolongation > cardiac arrest.
• With β blockers, CCBs, digitalis and antidepressants –
exaggerated bradycardia or arrythmias.
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ARTEMISININ DERIVATIVES
• Artemisinin is active principle of plant artemisia annua used
in chinese traditional medicine as “Quinghaosu”.
• Sesquiterpine lactone active against Pf resistant to all other
antimalarial.
• Prodrug, active metabolite - dihydroartemisinin
• Potent & rapid blood schizontocide > quicker defervescence &
parasitaemia clearance (< 48hr).
• Poor soluble in water & oil.
Artemether – soluble in oil
Artesunate – soluble in water.
arteether – soluble in chloroform.
• Don’t kill hypnozoites but have action on gametes.
• Fastest acting but short duration of action.
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• MOA –
functional group – endoperoxide bond > release of free radicals
species > binds to membrane proteins > lipid peroxidation,
damages ER > inhibit protein synthesis & ultimately lysis of
parasite.
1. Artesunate – oral absorption is incomplete but fast reaching peak
serum level within 1 hr & persist for upto 4 hrs.
 Dihydroartemisinin t1/2 is < 2 hrs
2. Artemether – oral or i.m. only.
 Slow oral absorption – 2-4 hrs
 Plasma t1/2 is 3-10 hrs
3. Arteether - i.m. only
 Plasma t1/2 23 hrs
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 SIDE EFFECTS
 abnormal bleeding, dark urine,
 S-T segment changes, QT prolongation, 1st degree A-V block,
 transient reticulopenia & leucopenia.
 Anaphylaxis, urticaria
 INTERACTIONS
 Co administration with terfenadine, astemizole, antiarrhythmics,
TCA & phenothiazines - ↑ risk of cardiac conduction defects.
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ARTEMISININ BASED COMBINATION THERAPY(ACT)
• WHO recommended ACT for acute uncomplicated resistant
falciparum malaria.
• Artemisinin reduces parasite load rapidly & drastically killing
>95% plasmodia.
• Leave only small biomass of parasites > eliminated by long t1/2
drug, reducing the chances of selecting resistant mutants.
 ADVANTAGES OF ACT
1. Rapid clinical & parasitological cure.
2. High cure rates (>95%) and low relapse rate.
3. Absence of parasite resistance (components prevent
development of resistance to each other).
4. Good tolerability profile.
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VARIOUS ACT REGIMENS
1. Artesunate-Sulfadoxine + Pyrimethamine
2. Artesunate-Mefloquine
3. Artesunate-Lumefantrine
4. Artesunate-Amodiaquine
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1. ARTESUNATE-SULFADOXINE + PYRIMETHAMINE (AS/S/P)
• 1st line drug for falciparum malaria in chloroquine resistant
areas under the NAMP of india .
• But it is not effective against multidrug-resistant strains which
are non responsive to S/P.
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• Recommended dose of artesunate – 4mg/kg/bw once a day x
3 days
• Recommended dose of S/P – single dose of 25mg/Kg of
Sulfadoxine and 1.25mg/Kg of pyrimethamine
• Dosage regimen recommended by NVBDCP for co-package is
as follows
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2. ARTESUNATE-MEFLOQUINE (AS/MQ)
• extensively used in Thailand, Myanmar
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3. ARTEMETHER-LUMEFANTRINE
• LUMEFANTRINE – orally active, high efficacy, long acting
erythrocytic schizontocide
• MOA ≈ Halofantrine and Mefloquine.
• No exoerythrocytic action
• Highly lipophilic – absorption starts after 2 hrs of ingestion and
peaks at 6-8 hrs.
• Plasma protein binding – 99% & Metabolized by CYP3A4
• Terminal t1/2 of 2-3 days, prolonged to 4-6 days in malaria pt.
• Lumefantrine used only in combination with artemether & is only
ACT available as fixed dose combination tablets.
• 80mg Artemeter BD with 480mg Lumefantrine BD for 3 days
• Two components protects each other from plasmodial resistance.
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• Gametocytes are rapidly killed, cutting down transmission.
• Oral – well tolerated.
 SIDE EFFECTS
• Headache, dizziness, sleep disturbances, abdominal pain, arthralgia, pruritus
and rash.
 INTERACTIONS
• Not given with metoprolol, neuroleptics, TCA etc.
• Contraindicated in 1st trimester of pregnancy & during breast feeding.
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TETRACYCLINES
• Slow acting, weak erythrocytic schizontocidal action against
plasmodial species.
• Pre-erythrocytic stage of Pf is inhibited.
• Tetracycline 250 mg QID or Doxycycline 100mg OD.
• Doxycycline 200 mg/day combined with artesunate to treat
mefloquine / chloroquine / S / P – resistant falciparum malaria
in Thailand.
• Used as short term chemoprophylaxis for upto 6wks.
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PROGUANIL
• Slow acting erythrocytic schizontocide & also inhibit
preerythrocytic stage of Pf.
• Gametocytes exposed to proguanil are not killed but fail to
develop properly in the mosquito.
• It is cyclized in body to triazine derivative (cycloguanil) which
inhibits plasmodial DHFRase in preference to mammalian
enzyme.
• PHARMACOKINETICS
• Slowly but adequate absorbed form gut.
• Partly metabolized & excreted in urine.
• Plasma t ½ of 16-20 hr
• SIDE EFFECT
• Mild abdomen upset, vomiting, haematuria, rashes and
transient loss of hair.
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ATOVAQUONE
• Synthetic naphthaquinone
• Rapidly acting erythrocytic schizontocide for Pf.
 MOA
collapses plasmodial mitochondria membranes
interferes with ATP production.
• Proguanil potentiates antimalarial action and prevents
emergence of resistance.
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COMPARATIVE PROPERTIES OF ANTIMALARIAL DRUGS
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 Antimalarial drugs exihibit considerable stage selectivity of action.
 AMT is given in following forms
1. CAUSAL PROPHYLAXIS
 Pre-erythrocytic phase in liver > cause of malarial infection
& clinical attacks > target for this purpose.
 Primaquine – causal prophylactic for all species of malaria.
2. SUPPRESSIVE PROPHYLAXIS
 Schizontocides which suppress erythrocytic phase and thus
attacks of malarial fever can be used as prophylactics.
 Exoerythrocytic phase in vivax & other relapsing malarias
continues, but clinical d/s does not appear.
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1. CHLOROQUINE -
 Prophylaxis only in areas with chloroquine sensitive Pf or Pv.
 300mg(base) PO once weekly.
 Begin 1-2 wks before travel to malarious areas.
 Take wkly on the same day of the week.
 And for 4 weeks after leaving such areas.
2. PROGUANIL –
 Areas with chloroquine or mefloquine resistant Pf.
 100mg PO daily – begin 1-2 days before travel &
for 7 day s after leaving the areas.
3. DOXYCYCLINE –
 Areas with chloroquine or mefloquine resistant Pf.
 100mg PO OD (1.5kg/kg/day) – begin 1-2 days before travel &
for 4 wks after leaving the areas.
 Not recommended for pregnant, lactating & child < 8 yrs.
4. MEFLOQUINE -
 Areas with chloroquine resistant Pf.
 250mg PO (5mg/kg/wk) once weekly.
 Begin 1-2 days before travel & for 4 wks after leaving the areas.
 Not recommended for pt with CNS disorder, psychiatric disturbances and
cardiac abnormalities. 33

3. CLINICAL CURE
• Erythrocytic schizontocides are used to terminate an episode of
malarial fever.
1) FAST-ACTING HIGH EFFICACY DRUGS-chloroquine,
amodiaquine, quinine, mefloquine, halofantrine,
lumefantrine, atovaquone, artemisinin.
2) SLOW-ACTING LOW-EFFICACY DRUGS-proguanil,
pyrimethamine, sulfonamides, tetracyclines.
4. RADICAL CURE
 Drugs which attacks the exoerythrocytic stage, given together with
clinical curative, achieve total eradication of parasite from patient’s
body.
 DOC for radical cure of vivax & ovale malaria - PRIMAQUINE 15mg
daily for 14 days.
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 No point in antirelapse treatment in highly endemic areas →
subsequent attack → erroneously labelled as failure of radical
cure.
 Antirelapse treatment of vivax malaria -
i. Areas with very low level of transmission
ii. During epidemic along with effective vector control measures to
cut down transmission.
5. GAMETOCIDAL
refer to elimination of male & female gametes of plasmodia formed
in pt’s blood → reducing transmission to mosquito.
PRIMAQUINE & ARTEMISININS CHLOROQUINE & QUININE
gametocidal to all species of plasmodia
active against vivax gametes
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In North-Eastern states (ACT-AL)
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TREATMENT OF SEVERE MALARIA
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SOME DON’TS IN SEVERE MALARIA
CASE MANAGEMENT
DO NOT
1) Use corticosteroids
2) Give iv mannitol
3) Use heparin as anticoagulant
4) Administer adrenaline
5) overhydrate
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VACCINE FOR MALARIA
RTS, S/ASO1 VACCINE
 Hybrid construct of the hepatitis B surface antigen fused with a
recombinant antigen derived from part of circum sporozoite
protein.
 Primarily for use in infants and young children in sub sahara
Africa.
 First malaria vaccine for use in some african countries as early as
2015.
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TREATMENT OF MALARIA - AIMS OF TREATMENT
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