ANTI MALARIAL DRUGS

Classification
Blood schizonticides:
Chloroquine, mefloquine, quinine, proguanil,
pyrimethamine, artemisinin derivatives,
lumefantrine, atovaquone, Doxycycline,
pyronaridine etc.
Tissue schizonticides: (exoerythrocytic pahse)
- Primary exoerythrocytic phase:
primaquine, atovaquone, proguanil
- Secondary exoerythrocytic phase: Primaquine
Gametocidal: Primaquine, artemisinin
derivatives
 Chloroquine
 A 4-aminoquinoline compound- erythrocytic
schizontocide against all species
 No effect on tissue phases of the parasite
 Does not prevent relapses (vivax & ovale)
MOA:
 Interfere with heme detoxification
 A weak base - accumulates in organism’s
acidic food vacuole
 Generates free radicals and iron bound
heme as highly reactive byproducts
 Chloroquine specifically binds to heme and
prevents its polymerization to hemozoin
 Oxidative damage to membrane, digestive
proteases or other biomolecules
 A chloroquine transporter glycoprotein
encoded by the “pfcrt” gene appears to
play a role in chloroquine resistance of P.
falciparum – other mech. are also possible
 This gene encodes a transporter in the
membrane of acidic vacuoles – efflux
chloroquine via an energy dependent
process
 Well absorbed by oral, i.m or s.c. routes
 Sequestrated in lung, spleen, liver, kidney,
melanin containing tissues etc.
 Terminal t/2 is 1
1--2 months
 A loading dose is required b’coz of extensive
tissue binding to get therapeutic conc.
 Metabolized by hepatic CYPs to two active
metabolites
 Renal excretion of parent & metabolites is
increased by acidification of urine
 ADRs
 Narrow safety margin drug
 Nausea, vomiting, anorexia, headache etc.
 Rapid i.v. inj-
inj- hypotension, arrhythmia,
cardiac arrest, confusion, seizure & coma
 High daily doses may result in retinotoxicity,
ototoxicity, toxic myopathy, neuropathy
 Avoid in epilepsy and M. gravis patients
 Use cautiously in liver/renal dysfunction,
severe GI or neurological disorders
 Can be used in pregnancy
 Hemolysis in G6PD deficiency (rare)
 It inhibits CYP2D6 – drug interactions
 Should not be given with mefloquine - ↑
risk of seizure and no added benefit
 Patient taking long
long--term, high dose
therapy should undergo eye and
neurological examination every 3- 3-6 mo
 DOC for clinical cure and suppressive
prophylaxis of all types of malaria, except
that caused by resistant P. falciparum
 DLE
 Rheumatoid arthritis
 Amoebiasis
 Mefloquine
 Highly effective blood schizonticide –
effective against chloroquine sensitive as
well as resistant plasmodia
 Very long t/2 (13-
(13-24 d); can cause
significant neuropsychiatric s/s in 10%
 Avoid in pregnancy or use if no alternative
 Contraindicated if, h/o seizure, MDI,
depression, neuropsychiatric conditions or
severe ADRs to other quinolines
 With halofantrine or quinine - ↑ QTc
 Quinine
 More toxic and less effective than
chloroquine
 Erythrocytic schizontocide for all species of
plasmodia
 Chloroquine and MDR strains of P.
falciparum respond
 MOA – similar to chloroquine
 Metabolized by CYP3A4 (20% excreted
unchanged in urine)
 t/2 increases in malaria based on severity
(due to ↓ clearance mainly) to 18 hrs
 Higher peak levels achieved in malaria with
lower toxicity (↑ α1 acid GP, less free drug)
 Dose related toxicities are – hypoglycemia
hypoglycemia,,
hypotension;
hypotension; Cinchonism - tinnitus,
nausea, vomiting (gastric irritation and CTZ
stimulation), headache, vertigo, difficulty in
hearing and vision (direct neurotoxicity +
constriction of retinal and auditory vessels)
 Diarrhoea, flushing and perspiration also
 Reversible if the drug is stopped
 Discontinue if evidence of hemolysis
appears
 Appears to be safe in pregnancy
 Used orally for uncomplicated and iv for
complicated/ cerebral malaria (chloroquine
sensitive or resistant)
Proguanil & pyrimethamine
 Erythrocytic schizontocide; proguanil also
inhibits primary exoerythrocytic phase
 Proguanil cyclizes in the body to a triazine
derivative (cycloguanil) which inhibits
plasmodial DHFRase
 Pyrimethamine is a directly acting inhibitor
of plasmodial DHFRase
 Primaquine
 An 8- aminoquinoline compound- Inactive
against erythrocytic schizonts
 Highly effective on primary as well as secondary
(hypnozoites) tissue (liver) phases
 Gametocidal for all species
 MOA: not clear; may be generation of reactive
oxygen species and/or interference with
mitochondrial electron transport
 t/2 (avg. 7 hrs); not a cumulative drug
 Induces CYP1A2 (may interact with warfarin)
 ADRs:
 Dose related haemolysis (mainly in G-6-PD
deficiency), methaemoglobinaemia (severe
in NADH MetHb reductase deficiency) - due
to the oxidant property of primaquine
Artemisinin derivatives (Artesunate,
Artemether, Arteether)
 Active against sensitive & MDR P. falciparum strains
 Potent and rapid blood schizonticide
 More rapid parasite clearance & fever resolution
 Action on a wide range of parasite blood stages -
broadest time window of antimalarial action
 Artemether is oil & Artesunate is water soluble
 MOA: free radicals within food vacuoles following
cleavage of the drug’s endoperoxide bridge by
heme Fe in parasitized RBCs
 DOA is short and recrudescence rate is
high (if used alone in short courses)
 Monotherapy needs to be extended
beyond the disappearance of the parasites
to prevent recrudescence
 Can be totally prevented by combining 3
day artesunate/artemether with a long-
acting drug
 Artesunate: administered oral, im or iv
 Rapidly converted to the active metabolite
dihydroartemisinin (DHA)
 The t/2 of DHA is 1-2 hours
 After repeated dosing, causes autoinduction
of its own metabolism (3A4, 2B6)
 Artemether: administered orally/im, not
iv
 Substantial 1st pass metabolism to DHA
 Arteether: for complicated/ cerebral
malaria (im); longer elimination t/2 (23
hours), effective in a 3 day schedule with a
recrudescence rate of 5%
 Recent (2006) WHO Regional guidelines for
SE Asia recommend a 5 day course
 ACTs should not be used in children <5 kg
and during 1st trimestar of pregnancy
 Lumefantrine
 Orally active, high efficacy, long-acting
erythrocytic schizontocide
 Acts in food vacuole to inhibit heme
polymerization
 Metabolized predominantly by CYP3A4
 Inhibits isoenzyme CYP2D6
 Terminal t/2 is 2-3 days, (prolonged to 4-6
days in malaria patients)
 Used only in combination with artemether
 Only ACT currently available as FDC tablets
 Active in MDR including mefloquine resistance
 Artemether quickly reduces parasite burden,
lumefantrine prevents recrudescence
 Not given with drugs metabolized by CYP2D6, or
with drugs which prolong QTc interval
 Contraindicated in first trimester of pregnancy and
during breastfeeding
 Atovaquone
 Highly lipophilic analog of ubiquinone
 Active against P falciparum blood and liver stages
 Act by disrupting mitochondrial electron transport
 Proguanil is synergistic and prevents resistance
 BA is low but increased by food – mostly eliminated
unchanged in feces; t/2 = 2-2-3 d
 Also used in treatment of P jiroveci and T. gondii in
AIDS
 Objectives of therapy
 To prevent and treat clinical attack of
malaria
 To completely eradicate the parasite from
the patient's body
 To reduce the human reservoir of infection
- cut down transmission to mosquito
Forms of antimalarial therapy
 Causal prophylaxis: drugs affecting
primary exoerythrocytic phase, the cause of
malaria is target for such drugs
- Proguanil: mainly for falciparum (given
daily) & not very effective against vivax
- Primaquine: prophylactic for all species
of malaria; used only for subjects
who cannot take other prophylactic drug
 Suppressive prophylaxis
 Drugs suppressing erythrocytic phase and thus attacks
of malarial fever
- Chloroquine base 300mg 5mg/kg/wk; Start 1-2
week before and continue till 4 wks after return
- Proguanil 200 mg daily with chloroquine 300 mg
weekly
- Mefloquine 250 mg weekly (1-2 wks before) and
till 4 weeks after return
- Doxycycline 100 mg daily starting 1-2 day before
travel and taken till 4 weeks after return
 Clinical cure
 The blood schizonticides are used to
terminate an episode of malarial fever
 Fast-acting high-efficacy drugs:
Chloroquine, quinine, mefloquine, artemisinin
etc.
 Slow-acting low-efficacy drugs:
Proguanil, pyrimethamine, tetracyclines etc.
 Radical cure
 Drugs which attack hypnozoites given
together with a clinical curative achieve total
eradication of the parasite
 Needed in relapsing malaria (vivax & ovale)
 Primaquine 15mg daily for 14 days
 Gametocytocidal
 Elimination of gametes in the patient's
blood
 No benefit to the patient but reduce the
transmission to mosquito
 Primaquine and artemisinins are
gametocidal to all species of Plasmodia
 A single 45 mg (0.75 mg/kg) dose of
primaquine base in falciparum malaria to
kill the gametes
 Not necessary when an artemisinin is used
for clinical cure
 Treatment regimens
P. vivax malaria
 Chloroquine base: 10mg/kg (600mg) on
day 1, 10mg/kg (600mg) on day 2 and
5mg/kg (300 mg) on day 3
+
 Primaquine base: 0.25 mg/kg body weight
(15mg) daily for 14 days from day 1

Reference: NATIONAL DRUG POLICY ON MALARIA (2010)

 Uncomplicated P. falciparum
malaria
 Artemisinin Combination Therapy (ACT)
should be given to all confirmed P. falciparum
cases found positive by microscopy or RDT
Artesunate 4 mg/kg body weight daily for 3
days +
Sulfadoxine (25 mg/kg; 1500mg) and Pyri-
methamine (1.25 mg/kg; 75mg) on Day 1 +
Primaquine base (0.75mg/kg; 45 mg) on
day 2
 Uncomplicated P. falciparum cases in
pregnancy
 1st Trimester: Quinine salt* 10mg/kg 3 times
daily for 7 days
 2nd and 3rd trimester: ACT as per dosage
described in earlier slide
 P. vivax malaria can be treated with chloroquine

*Quinine may induce hypoglycemia; pregnant

women should not start taking quinine on an
empty stomach and should eat regularly
 Treatment of mixed infections (P. vivax
+ P. falciparum) cases
 Full course of ACT and Primaquine base
(0.25mg per kg body weight;15mg) daily for
14 days
Complicated/Severe malaria
 Artesunate: 2.4 mg/kg BW IV or IM given on
admission (time = 0 h); then at 12 h and 24 h
and then once a day
or
 Artemether: 3.2 mg/kg BW IM given on
admission and then 1.6 mg/kg body weight per
day
or
 Arteether: 150 mg IM daily for 3 days in adults
only (not recommended for children)
or
 Quinine: 20 mg/kg* body weight on admission (IV
infusion or divided IM injection) followed by
maintenance dose of 10 mg/kg BW 8 hourly
 The infusion rate should not exceed 5 mg salt/kg
body weight per hour
 Loading dose of 20 mg/kg body weight should not
be given, if the patient has already received quinine
 NEVER GIVE BOLUS INJECTION OF QUININE
 If parenteral quinine therapy needs to be continued
beyond 48 hours, dose should be reduced to 7 mg/
kg body weight 8 hourly
 Parenteral therapy should be given for
minimum of 24 hours once started
(irrespective of the patient’s ability to
tolerate oral medication earlier than 24 hrs)
 After parenteral artemisinin therapy, patients
will receive a full course of oral ACT for 3
days (ACT containing mefloquine should be
avoided in cerebral malaria due to neuro-
psychiatric complications)
 Those patients who received parenteral
Quinine therapy should receive:
Oral Quinine 10 mg/kg body weight three
times a day for 7 days (including the days
when parenteral Quinine was administered)
plus Doxycycline 3 mg/kg body weight
once a day or Clindamycin 10 mg/kg body
weight 12-hourly for 7 d
*Severe malaria is an emergency and treatment
should be given promptly; Parenteral artemisinin
derivatives or quinine should be used
irrespective of chloroquine sensitivity

*Severe malaria caused by P. vivax should be

treated like severe P. falciparum malaria
 Chemoprophylaxis
Short term chemoprophylaxis (up to 6 wks)
 Doxycycline: 100 mg OD for adults (1.5
mg/kg OD) for children >8 years - started 2
days before travel and continued for 4 weeks
after leaving the malarious area
Chemoprophylaxis (more than 6 wks)
 Mefloquine: 250 mg weekly for adults and
should be administered 2 weeks before, during
and 4 weeks after exposure
 Other ACTs
Artesunate
Artesunate--mefloquine
Artesunate 100 mg BD (4mg/kg/day) for 3
days + Mefloquine 750 mg (15mg/kg) on
day 2 and 500 mg (10 mg/kg) on day 3
Artemether-
Artemether-lumefantrine (1:6 ratio)
Artemether 80mg BD + Lumefantrine 480
mg BD for 3 days (to be taken with fatty
meal)
Regimens for chloroquine resistant
falciparum malaria
 Artesunate 100 mg BD X 3 days +
Sulfadoxine 1500mg & Pyrimathamine 75 mg as
single dose
 Artesunate 100 mg BD X 3 days + Mefloquine
750 mg on day 2 and 500 mg on day 3
 Atremether 80 mg & lumefantrine 480 mg BD
for 3 days
 Quinine 600 mg TID X 7 days + Doxycycline 100
mg OD X 7 days
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